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1
Millar, Christopher G. "Endothelial progenitor cells and vascular injury". Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/24977.
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Endothelial progenitor cells (EPCs) are bone marrow derived cells that contribute towards neovascularisation. I have primarily used real time polymerase chain reaction (PCR), but also flow cytometry and cell culture techniques, to investigate the effect of vascular injury on the expression of the putative markers of EPCs (CD34, CD133, VEGFR-2 and VE-cadherin) and their number in peripheral blood. In the first study I investigated the effect of percutaneous coronary intervention (PCI) on EPCs in a group of patients with stable coronary disease. After PCI, EPC markers did not conclusively demonstrate a rise in expression, although the number of VEGFR-2+ cells did increase. However, the number of EPC colony forming units (CFUs) increased significantly. In the next study, I investigated the effect of open aortic aneurysm repair on EPCs in a group of elective surgical patients. There were changes in the level of expression of EPC markers, using both real-time PCR and flow cytometry, but statistical significance was not reached. However, there were significant increases in the mean fluorescent intensities (MFI) of VEGFR-2 and VE-cadherin expression. EPC-CFUs did not change significantly. The next study investigated the effect of type 1 diabetes on EPC levels. The percentage of CD34+ cells, the RQ of VE-cadherin mRNA and the number of EPC-CFUs were significantly reduced in the diabetic cohort compared with control groups. Finally, the effect of chronic renal impairment and administration of human recombinant erythropoietin (Epo) on EPC levels was investigated. The RQs of CD34, VEGFR-2 and VE-cadherin mRNA species increased over the period analysed, but this increase did not correspond with an increase in VEGF expression. This thesis provides further insight into the effect of endogenous and exogenous causes of vascular injury on EPCs.
2
Mallawaarachchi, Chandike Maithri. "The adventitial response to vascular injury". Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619944.
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Matter, Christian M. "Molecular and cellular mechanisms of vascular injury /". Zürich, 2007. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253379.
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Macdonald, Linsay Joanne. "Glucocorticoid metabolism and the vascular response to injury". Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/24084.
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In order to study the influence of glucocorticoids on vascular lesion formation, a model of intra-luminal, wire-induced vascular injury in the mouse femoral artery was developed. This model caused extensive stretching of the arterial wall and denudation of the endothelium, followed by the time-dependent formation of smooth muscle-rich neointimal lesions. Systemic administration of dexamethasone by sub-cutaneous injection (1 mg/kg/day, 21 days) reduced the size of smooth muscle-rich lesions after injury, but also promoted the formation of large thrombotic lesions. These occluded the lumen, leading to a similar reduction in luminal diameter to that seen in vehicle-treated controls. In contrast, local application of cortisol at the vessel wall via sustained release from an implanted pellet (21 days), significantly reduced neointimal lesion growth when compared to contra-lateral vehicle controls, without the development of thrombotic lesions. The influence of endogenous glucocorticoid activity on neointimal proliferation in the femoral artery was assessed using administration of a glucocorticoid receptor antagonist (RU38486, via implanted pellet for 21 days) or via selective pharmacological inhibition of 11βHSD1 (60mg/kg/day via oral gavage, 14 days) and the use of mice with transgenic disruption of 11βHSD1. Neither glucocorticoid receptor antagonism nor 11βHSD1 inhibition or deletion altered neointimal lesion development after injury. These results indicate that exogenous glucocorticoids do inhibit proliferation in this model but their effectiveness depends upon whether they are administered systemically or locally at the vessel wall. Whereas the manipulation of endogenous glucocorticoid generation in the vessel wall may not represent a novel therapeutic target, the application of glucocorticoids locally at this site may be beneficial in the treatment of arterial remodelling.
5
Wahlgren, Carl Magnus. "Mechanisms of thrombosis and restenosis after vascular injury /". Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-260-8/.
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Bundy, Ruth Eldeca. "Redox modulation of vascular cell injury and adaptation". Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414511.
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Hay, Jennifer R. "Vascular and cellular responses to traumatic brain injury". Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/30819/.
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There is growing evidence that suggests Traumatic brain injury (TBI) may initiate long-term neurodegenerative processes. Exposure to a single moderate or severe TBI, or to repetitive TBI, reveals a complex of pathologies including abnormalities of tau, amyloid-β and TDP-43; neuronal loss; neuroinflammation; and white matter degradation. The mechanisms driving these late post-TBI neurodegenerative pathologies remain elusive. Firstly, a potential association between blood-brain barrier (BBB) disruption and TBI was investigated. Results showed that increased and widespread BBB disruption was observed in material from patients dying in the acute phase following a single, moderate to severe TBI and persisted in a high proportion of patients surviving years following injury. Furthermore, there was preferential distribution to the deep layers of the cortex and to the crests of the gyri rather than the depths of the sulci. This post-TBI BBB disruption was investigated further within a paediatric TBI cohort. BBB disruption was noted in both paediatric and adult TBI in a similar pattern and distribution, however, interestingly, in sharp contrast to adult TBI cases, BBB disruption in paediatric cases appears preferentially distributed to capillary sized vessels. This vulnerability of the small vessels was rarely observed in adult material. In addition to the post-TBI vascular change observed, the cellular response was investigated, which interestingly, demonstrated regional differences. Specifically, in the grey matter, reactive astrogliosis was observed subpially, around cortical vessels, at the grey and white matter boundaries and subependymally. This astrogliosis was evident in a proportion of acute and continued into the late phase following TBI. In contrast, microglial activation was observed as a delayed response and localised to the white matter tracts. In addition, this delayed microglial response expressed an M2-like phenotype. Furthermore, there was an increased population of inactivated perivascular microglia beyond the perivascular space in the grey matter regions, observed in the acute phase and persisted in a proportion of patients surviving years following injury. Collectively these findings are interesting and indicate TBI induces both a vascular and cellular responses which may contribute to the long-term post-TBI neurodegenerative processes.
8
Oommen, Anson Jacob. "Assessing the role of Polyphenols as a vascular protectant against Drug Induced Vascular Injury". Wright State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=wright1560292217772559.
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Kahn, Matthew Benjamin. "Effects of insulin resistance on endothelial regeneration following vascular injury". Thesis, University of Leeds, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.550287.
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Insulin resistance, the primary metabolic abnormality underpinning type 2 diabetes mellitus and obesity, is an important risk factor for the development of cardiovascular disease. Endothelial dysfunction represents one of the earliest phases in the natural . history of atherosclerosis and is normally offset in health by various endogenous repair processes. Circulating endothelial progenitor cells (EPCs) participate in endothelial repair following arterial injury. Type 2 diabetes is associated with fewer circulating EPCs, EPC dysfunction and impaired endothelial-repair. I set out to determine whether insulin-resistance per se adversely affects EPC mediated endothelial-regeneration using mice hemizygous for knockout of the insulin receptor (IRKO) and wild-type (WT) littermate controls. The metabolic phenotype of IRKO mice was consistent with compensated insulin resistance. Flow cytometry demonstrated that IRKO mice had fewer circulating EPCs than WT mice. Culture of mononuclear-cells confirmed that IRKO mice had fewer EPCs in peripheral-blood, but not in bone-marrow or spleen, suggesting a mobilization defect. Defective VEGF-stimulated EPC mobilization was confirmed in IRKO mice, consistent with reduced eNOS expression in bone marrow and impaired vascular eNOS activity. Paracrine angiogenic activity of EPCs from IRKO mice was impaired compared to those from WT animals. Endothelial-regeneration of the femoral artery following denuding wire-injury was delayed in IRKO mice compared to WT. Transfusion of mononuclear-cells and c-kit bone-marrow cells from WT mice normalized the impaired endothelial-regeneration in IRKO mice. However, transfusion of c-kit+ cells from IRKO mice was less effective at improving endothelial-repair. My data suggest that insulin-resistance impairs EPC function and delays endothelial-regeneration following arterial injury. These findings support the hypothesis that insulin-resistance per se is sufficient to jeopardise endogenous vascular repair. Defective endothelial-repair may be normalised by transfusion of EPCs from insulin- sensitive animals but not from insulin-resistant animals. These data may have important implications for the development of therapeutic strategies for insulin- resistance associated cardiovascular disease.
10
Evans, Steven Martin. "Role of nitric oxide isoenzymes in inflammation and vascular injury". Thesis, King's College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267851.
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Greig, Fiona Helen. "The involvement of modified lipids in vascular injury and disease". Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4229/.
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Atherosclerosis is characterised by the deposition and accumulation of modified lipids in the subendothelial space of the arterial wall, as well as vascular remodelling leading to atherosclerotic plaque formation. Restenosis is a known complication of the surgical interventions used to treat atherosclerosis and results in neointimal thickening, in part by the action of vascular smooth muscle cells (VSMCs). Various physiological effects have previously been attributed to the action of oxidised low density lipoproteins leading to an exacerbation of the inflammatory response and vascular remodelling processes in atherosclerosis and restenosis. Little is known to date about the effects of individual modified lipids generated by the action of phagocytic myeloperoxidase (MPO) on these processes. The aim of the present study was to investigate the biological effects of modified lipids, both chlorinated and oxidised species, in vascular injury and disease, focussing primarily on their effects on vascular smooth muscle (VSM). Primary VSMCs were used to examine the effects of these modified lipids at a cellular level. Chlorinated lipids, phospholipid chlorohydrins and alpha-chloro fatty aldehydes were found to have a limited effect on VSMC proliferation, viability or migration whereas, oxidised phospholipids caused a concentration-dependent reduction in all of these vascular remodelling processes. As AMP-activated protein kinase (AMPK) has recently been implicated in vascular disease and found to exert anti-apoptotic effects, the impact of AMPK signalling on the effects of the modified lipids in VSM was assessed. Activation of AMPK prior to incubation of 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine chlorohydrin resulted in an increase in VSMC proliferation while a greater level of VSMC death was observed after treatment with the oxidised phospholipid, 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphocholine than with the lipids alone. The occurrence of these modified lipids in neointima formation was subsequently investigated using a carotid artery injury model in healthy and atherosclerotic mice (mice deficient in apolipoprotein E, ApoE-/-). Neointimal growth and levels of plasma MPO were increased in ApoE-/- mice resulting in elevated levels of lysophosphatidylcholines and altered relative proportions of phosphatidylcholines (PCs) in injured carotid arteries compared to their contralateral uninjured right carotid arteries. Finally, in vivo AMPK activation by administration of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) in healthy and atherosclerotic mice and its effect on the lipid profile of the aorta were characterised. Chronic AMPK activation resulted in a reduction in mean arterial and diastolic pressures as well as a dramatic increase in pulse pressure in ApoE-/- mice compared to their saline-treated littermates. Plasma MPO was elevated in AICAR-treated ApoE-/- mice with an alteration in the relative intensities of PCs in aortae of AMPK activated ApoE-/- mice. The present study is the first report of divergent effects of different classes of modified lipids on vascular remodelling processes and how these processes may be modulated by AMPK signalling in VSM in atherosclerosis. In addition, this study has generated novel data on the relative changes in distribution of PCs in carotid arteries after vascular injury as well as in aortic tissue of healthy and atherosclerotic mice after AMPK activation. Additional analysis is required to confirm these differences which could offer further insight into the involvement of modified lipids in vascular diseases. This study has also highlighted a novel interaction of AMPK signalling and modified lipids in VSM and could therefore provide novel therapeutic targets in the treatment of both atherosclerosis and restenosis.
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Kirkby, Nicholas S. "Investigating the role of endothelin receptor subtypes in the response to vascular injury". Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4440.
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Neointimal hyperplasia, the proliferative growth of the innermost layer of the blood vessel wall, is a key process in the response to vascular injury, underlying conditions such as post-interventional restenosis and vein/arterial graft disease. One of the many mediators implicated in this process is endothelin-1 (ET-1), a potent vasoconstrictor with pro-inflammatory and pro-mitogenic actions, which acts through ETA and ETB receptor subtypes. It is well established that ET-1 increases, and ETA blockade reduces, neointima formation following vascular injury. The role of ETB is less clear because these receptors mediate potentially beneficial actions in endothelial cells (EC; such as nitric oxide production, and ET-1 clearance) but detrimental effects elsewhere (such as vascular smooth muscle) and it has been recently reported that non-cell-specific ETB deficiency is associated with increased neointimal lesion size following injury. The work described in this thesis addressed the hypothesis that endogenous ET-1 contributes to neointimal hyperplasia by activation of the ETA receptor, and that this action is moderated by concurrent activation of the ETB receptor expressed in EC. The role of ET receptors in neointimal lesion development was assessed using two models of femoral arterial injury in the mouse: (i) an established method of intraluminal wire-injury, and (ii) adaptation of a model of ligation injury that induces robust neointimal lesion formation without physical damage to the endothelium. Lesion development was assessed using standard histological techniques and this was augmented by development of quantitative optical projection tomography (OPT) to allow three-dimensional analysis of lesions. The role of ETA and ETB receptors in these models was addressed using suitable pharmacological ET receptor antagonists. Following wire-injury, selective ETB blockade (A192621; 30mg.kg-1.day-1; 35 days) increased lesion size and blood pressure without significant altering lesion composition. In contrast, selective ETA blockade (atrasentan; 10mg.kg-1.day-1; 35 days) reduced lesion size and blood pressure. Combined ETA+ETB antagonism had no effect on lesion size, despite reducing blood pressure, and reducing collagen content of the lesions. In the ligation model, neither ETA selective, ETB selective nor ETA+ETB blockade altered lesion size as assessed by standard histology but analysis by OPT indicated that ETA blockade, with or without concurrent ETB blockade, reduced lesion volume. The influence of ETB receptors expressed by ECs on lesion formation was addressed using EC-specific ETB knockout mice. Small vessel myography indicated that endothelium-dependent relaxation was unaltered in femoral arteries from these mice. In addition, no effect on lesion size or rate of development was observed in either wire- or ligation-injury models of neointima formation (although subtle effects on lesion and medial composition were apparent after intra-luminal injury). These results indicate that ETB receptor activation can moderate the detrimental actions of the ETA receptor on neointimal lesion progression, and that this role is dependent on the mode of vascular injury. Furthermore, in this setting, this beneficial action is not primarily mediated by ETB expressed by EC, suggesting that ETB in other cell types can reduce lesion development through another, unidentified mechanism. Therefore, while both ETA selective and non-selective ETA/B antagonists are currently in clinical use, in conditions where similar arterial remodelling processes occur, selective ETA receptor antagonists might be preferred.
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Rafi-Janajreh, Asimah. "Role of CD44 in Immune Functions and Endothelial Cell Injury". Diss., Virginia Tech, 1998. http://hdl.handle.net/10919/77996.
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In addition to the antigen-specific receptors, the T and B cells also express a variety of adhesion molecules, which are known to participate in cell-cell interaction, migration, homing and signal transduction. CD44 is a widely distributed cell surface glycoprotein whose principal ligand has been identified as hyaluronic acid (HA), a major component of the extracellular matrix. In the current study, we investigated whether HA or mAbs against CD44 would induce a proliferative response in mouse lymphocytes. Spleen cells from normal and nude but not severe combined immunodeficient mice, exhibited strong proliferative responsiveness to stimulation with soluble HA or anti-CD44 mAbs. Furthermore, purified B cells but not T cells were found to respond to HA. These data demonstrated that interaction between HA and CD44 can regulate murine B cell effector functions and that such interactions may play a critical role during normal or autoimmune responsiveness of B cells.
Endothelial cell injury resulting in vascular leak syndrome (VLS) is one of the most widely noted phenomenons in a variety of clinical diseases, however, the underlying reason for which remains unclear. We used interleukin-2 induced VLS as a model to investigate the role of cytolytic lymphocytes in the direct cytotoxicity of endothelial cells. BL/6 wild-type mice developed significant VLS in the lungs, liver and spleen following IL-2 administration. Interestingly, perforin-knockout mice exhibited marked decrease in VLS in all three organs tested. Also, FasL-defective (gld) mice and Fas-deficient (lpr) mice exhibited decreased VLS in the liver and spleen, but not in the lungs. These results demonstrated for the first time that perforin and FasL may actively participate in endothelial cell injury and induction of VLS in a variety of organs.
Inasmuch as, CD44 also plays a major role in the lymphocyte adhesion to the endothelial cells, we used CD44-knockout mice and observed that such mice exhibited markedly diminished VLS following IL-2-treatment. Our data also suggested that blocking CD44 helps in reducing the IL-2-induced VLS and therefore such an approach may serve as a useful tool to prevent endothelial cell damage seen in a variety of clinical disorders.Ph. D.
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Amaro, Emilie, Stephen Pophal i Jozef Zoldos. "Vascular Reconstruction in a Neonate after Iatrogenic Injury during Cardiac Catheterization". LIPPINCOTT WILLIAMS & WILKINS, 2017. http://hdl.handle.net/10150/627070.
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As technology and interventional techniques continue to evolve, both the volume and complexity of cardiac catheterizations will increase, leading to a rise in the number of complications. One of the most morbid complications of cardiac catheterization is vascular injury. We report the case of a 31-day-old, 3.0-kg infant with hypoplastic left heart syndrome who experienced a left common iliac artery disruption during cardiac catheterization resulting in a retroperitoneal hemorrhage. The extent of the vascular injury combined with the vessel caliber posed a technically challenging surgical scenario. Ultimately, the vascular supply to the left lower extremity was reconstructed by the plastic surgery team with a reverse autologous vein graft. To our knowledge, this multidisciplinary approach with the involvement of plastic surgery represents a unique case.
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Dollery, Clare Margaret. "Matrix metalloproteinase inhibitors in vascular injury : pharmacological and gene transfer approaches". Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286196.
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Lauder, Heather. "Role of endothelins and somatostatin in vascular cell regeneration following injury". Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627199.
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Padfield, Gareth John. "Role of endothelial progenitor cells in acute vascular injury in man". Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/8806.
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Percutaneous coronary intervention (PCI) acutely improves coronary blood flow and myocardial perfusion but at the expense of endovascular laceration and endothelial denudation. PCI associated vascular injury is associated with intense inflammation and a loss of vascular function that may lead to significant in-stent restenosis (ISR), and the potentially catastrophic, acute stent thrombosis. Reendothelialisation is essential to the restoration of normal homeostasis and facilitating vascular healing. Attention has recently focused on a novel mechanism of reendothelialisation mediated by bone marrow-derived precursor or stem cells: endothelial progenitor cells (EPC). EPC are thought to home to, and reendothelialise sites of endothelial denudation, and therefore offer the potential to provide exciting new developments in the management of cardiovascular disease. Understanding the role of EPC following vascular injury may help us to enhance vascular repair following PCI. The following studies were performed to clarify the relationships between putative EPC and vascular injury associated with PCI. In studies of patients undergoing elective PCI for stable anginal symptoms I found that concentrations of traditional circulating phenotypic EPC expressing CD34+VEGFR-2+ were unaffected, unlike CD34+CD45- cell concentrations, which were transiently increased six hours following PCI, subsequently returning to normal by 24 hours, notably without an increase in CD34+ adhesion molecule expression or VEGF-A production. However, the purported progeny of CD34+VEGFR-2+ cells, endothelial cell-colony forming units (EC-CFU), were mobilised at 24 hours, commensurate with a systemic inflammatory response. Interestingly the concentration of circulating CD34+VEGFR-2+ cells and EC-CFU were unrelated to each other, emphasising the distinction between these two cell populations. Although EC-CFU contained proliferating cells and exhibited some endothelial characteristics, EC-CFU predominantly expressed the leukocyte antigen CD45 in addition to the lymphocyte markers CD4 and CD8, and most intensely, the surface markers CD68 and CD105, epitopes commonly expressed on macrophages. Notably, EC-CFU were a potent stimulus for the migration of mononuclear cells. However, despite being mobilised in the context of an acute systemic inflammatory response and being composed of leukocytes, isolated systemic inflammation in healthy volunteers (induced by Salmonella Typhus vaccination) in the absence of vascular injury did not cause selective mobilisation of EC-CFU or indeed of putative phenotypic EPC. It is therefore likely that EC-CFU mobilisation is a relatively specific inflammatory response to cardiovascular injury. In a cohort of 201 patients undergoing coronary angiography, traditional circulating phenotypic EPC (CD34+VEGFR-2+ and CD34+VEGFR-2+CD133+) were very rare indeed and were not increased in response to an acute coronary syndrome (ACS). Furthermore traditional EPC concentrations bore no relation to atheroma burden or clinical outcome. In contrast, concentrations of CD34+CD45- cells were increased in patients with coronary artery disease compared to those with normal coronary arteries and were increased in association with more severe coronary disease. Increased concentrations of circulating CD34+CD45- cells were also associated with a shorter cumulative event-free survival. Both EC-CFU and angiogenic monocytes expressing Tie-2 and VEGFR-2 were increased following acute myocardial infarction but did not relate to coronary atheroma or clinical outcome. These studies examine the behavior of putative EPC in response to both discrete vascular injury and myocardial infarction, and isolated inflammation in the absence of vascular injury. I have identified novel characteristics of the EC-CFU assay and determined that specific factors associated with cardiovascular injury likely trigger EC-CFU mobilisation. The clinical relevance of the traditional phenotypic EPC population is uncertain, but a novel CD34+CD45- population is mobilised acutely following discrete vascular injury and is significantly associated with coronary atheroma and clinical events. It is probable that the circulating CD34+CD45- concentration reflects vascular injury and atheroma burden, and I suggest that CD34+CD45- cells are released directly from the vessel wall following PCI, and do not reflect a reparatory response. In order to determine the impact of EPC populations on vascular healing, prospective studies examining the impact of periprocedural EPC concentrations on vascular healing following PCI are required.
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MOORE, ZACHARY W. Q. "APOLIPOPROTEIN E MODULATION OF VASCULAR SMOOTH MUSCLE CELL RESPONSE TO INJURY". University of Cincinnati / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1127219075.
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Rudström, Håkan. "Iatrogenic Vascular Injuries". Doctoral thesis, Uppsala universitet, Kärlkirurgi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-194346.
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Iatrogenic vascular injuries (IVIs) and injuries associated with vascular surgery can cause severe morbidity and death. The aims of this thesis were to study those injuries in the Swedish vascular registry (Swedvasc), the Swedish medical injury insurance where insurance claims are registered, the Population and Cause of death registries, and in patient records, in order to explore preventive strategies. Among 87 IVIs during varicose vein surgery 43 were venous, mostly causing bleeding in the groin. Among 44 arterial injuries, only 1/3 were detected intraoperatively. Accidental arterial stripping predominated, with poor outcome. Four patients died, all after venous injuries. IVIs increased over time, and constitute more than half of the vascular injuries registered in the Swedvasc. Lethal outcome was more common (4.9%) among patients suffering IVIs than among non-iatrogenic vascular injuries (2.5%). Risk factors for death were age, diabetes, renal insufficiency and obstructive lung-disease. Fifty-two patients died within 30 days after IVI. The most common lethal IVIs were puncture during endovascular procedures (n=24, 46%), penetrating trauma during open surgery (11) and occlusion after compression (6). Symptoms were peripheral ischemia (n=19), external bleeding (14), and hypovolemic chock without external bleeding (10). Most died within two weeks (n=36, 69%). After >2 weeks the IVI as a cause of death was uncertain. Among 193 insurance claims after vascular surgery during 2002-2007, nerve injuries (91) and wound infections (22) dominated. Most patients suffered permanent injuries, three died. Patients with insurance claims were correctly registered in the Swedvasc in 82%. In 32 cases of popliteal artery injury during knee arthroplasty symptoms were bleeding (n=14), ischaemia (n=7) and false aneurysm formation (n=11). Only twelve injuries (38%) were detected intraoperatively. Patency at 30 days was 97%, but only seven (22%) patients had complete recovery. Six of those had intraoperative diagnosis of popliteal injury and immediate vascular repair. In conclusion, registration of IVIs is increasing and outcome is often negatively affected by diagnostic and therapeutic delay. Not all fatalities after IVIs are attributable to the injury itself. The most common causes of insurance claims after vascular surgery were nerve injuries, and 82% were correctly registered in Swedvasc.
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Mthethwa, Mashudu. "The responses of endothelium to insult : does endothelial heterogeneity play a role in in vitro cell models". Thesis, Stellenbosch : Stellenbosch University, 2015. http://hdl.handle.net/10019.1/97832.
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Thesis (PhD)--Stellenbosch University, 2015.ENGLISH ABSTRACT: Endothelial injury and dysfunction precede the development of cardiovascular diseases. The endothelium may be regarded as the first line of defence against inflammation / obesity-induced vascular injury, therefore gaining more information on the mechanisms of injury and response to injury, as well as modulating endothelial function may be key in the prevention of cardiovascular diseases. Endothelial cells differ in structure and function, therefore endothelial heterogeneity may be relevant when investigating endothelial function and dysfunction. Understanding endothelial heterogeneity in response to pathophysiological stimuli may be of significance in the prevention of cardiovascular diseases. Oleanolic acid (OA), a plant-derived triterpenoid, has been shown to possess endothelio-protective properties; however, its role in reversing endothelial injury is poorly understood. This study investigated endothelial heterogeneity between aortic endothelial cells (AECs) and cardiac microvascular endothelial cells (CMECs) at baseline and in response to an inflammatory insult via the cytokine, tumour necrosis factor-alpha (TNF-α). An in vitro model of endothelial injury was developed by treating AECs and CMECs with 20 ng/ml TNF-α for 24 hours. Endothelial heterogeneity was investigated by comparing intracellular nitric oxide (NO) and reactive oxygen species (ROS) production, protein expression and phosphorylation, and large-scale protein expression and regulation in AECs and CMECs. The experimental techniques included flow cytometry, western blots and proteomic analyses. An ex vivo model of endothelial injury was included to investigate vascular function in aortic rings from lean and high fat diet (HFD) rats. The role of OA in reversing TNF-α-induced injury and modulating vascular function in the ex vivo model was investigated. Although baseline NO-levels were similar between AECs and CMECs, heterogeneity was observed with regards to the NO biosynthetic pathway in terms of increased eNOS expression in CMECs. Baseline ROS levels were heterogeneous between AECs and CMECs, interestingly CMECs possessed higher anti-oxidant capacity. An in vitro model of TNF-α-induced injury was confirmed by decreased NO-levels, increased ROS-levels and necrosis, up-regulation of apoptotic proteins and activation of inflammatory pathways in AECs and CMECs. Here, heterogeneity between AECs and CMECs was also observed: endothelial activation was mediated through different proteins in AECs (CD9 molecule, galectin) and CMECs (ICAM-1 and IL-36α). Apoptosis was mediated by caspase 3 in AECs and Bid in CMECs. AECs appeared to advance to a dysfunctional state shown by up-regulation of endothelin-converting enzyme and angiotensin II-converting enzyme, while CMECs maintained an activated state. OA reversed TNF-α-induced injury through restoring NO-production, decreasing ROS-production in both AECs and CMECs, and inhibiting necrosis in AECs. In the ex vivo model of injury, aortic rings from 16-week HFD rats showed a pro-contractile response to phenylephrine-induced contraction, a response that was reversed by OA. In conclusion, we demonstrated novel findings with regards to endothelial heterogeneity between AECs and CMECs under baseline and TNF-α-treated conditions. Although reduced NO-bioavailability may be the hallmark of endothelial dysfunction, signalling pathways mediating endothelial injury may differ between cell types as was shown in this study. We demonstrated that OA possess protective properties in AECs and CMECS, an observation which was translated to the ex vivo model.
AFRIKAANSE OPSOMMING: Endoteelbesering en –disfunksie gaan die ontwikkeling van kardiovaskulêre siektes vooraf. Die endoteel word as die eerste linie van verdediging teen inflammasie / vetsug-geïnduseerde vaskulêre skade beskou; dus is die ontginning van nuwe inligting betreffende die meganismes van en respons tot besering, asook die modulering van endoteelfunksie essensieël in die voorkoming van kardiovaskulêre siektes. Endoteelselle verskil t.o.v. struktuur en funksie, en dus is endoteel-heterogeniteit relevant tydens die ondersoek van endoteelfunksie en –disfunksie. ‘n Beter begrip van endoteel-heterogeniteit in die respons tot patofisiologiese stimuli kan betekenisvol tot die voorkoming van kardiovaskulêre siektes bydra. Oleanoliese suur (OA), ‘n triterpenoïed afkomstig van plante is voorheen bewys om endoteelbeskermende eienskappe te besit; die rol van OA in die omkering van endoteelbesering is egter minder bekend. Hierdie studie het endoteel-heterogeniteit tussen aorta endoteelselle (AECs) en hart mikrovaskulêre endoteeelselle (CMECs) by basislyn en in respons tot ‘n inflammatoriese besering via die sitokien, tumor nekrose faktor-alfa (TNF-α), ondersoek. ‘n In vitro model van endoteelbesering is ontwikkel deur AECs en CMECs met 20 ng/ml TNF-α vir 24 uur te behandel. Endoteel-heterogeniteit was ondersoek deur intrasellulêre stikstofoksied (NO) en reaktiewe suurstofspesies (ROS) produksie, proteïenuitdrukking en fosforilering, en grootskaalse proteïenuitdrukking en regulering in AECs en CMECs te vergelyk. Die eksperimentele tegnieke het ingesluit: vloeisitometrie, western blots en proteomika. ‘n Ex vivo model van endoteelbesering was ook ingesluit deur die vaskulêre funksie in aortaringe van normale en hoë vet dieet-gevoerde (HFD) rotte te meet. Die rol van OA in die omkering van TNF-α-geïnduseerde besering en modulering van vaskulêre funksie was in hierdie model is ondersoek. Alhoewel basislyn NO-vlakke vergelykbaar was in AECs en CMECs, is heterogeniteit wel aangetoon m.b.t. die NO biosintese pad met verhoogde eNOS uitdrukking in die CMECs. Basislyn ROS-vlakke was verskillend in AECs en CMECs en die CMECs het hoër anti-oksidant kapasiteit getoon. ‘n In vitro model van TNF-α-geïnduseerde besering is bevestig met die waarneming van verlaagde NO-vlakke, verhoogde ROS-vlakke en nekrose, opregulering van apoptotiese proteïene en aktivering van inflammatoriese paaie in AECs en CMECs. Hier was heterogeniteit ook opmerkbaar: endoteelaktivering was deur verskillende proteïene in AECs (CD9 molekule, galektien) en CMECs (ICAM-1, IL-36α) bemiddel. Apotose was deur kaspase 3 in AECs en Bid in CMECs bemiddel. Dit het geblyk dat AECs tot ‘n staat van endoteeldisfunksie gevorder het met die opregulering van endotelien-omsettingsensiem en angiotensien II-omsettingsensiem, terwyl CMECs eerder ‘n geaktiveerde staat gehandhaaf het. OA het TNF-α-geïnduseerde besering omgekeer deur NO-produksie te herstel, ROS-produksie te onderdruk in beide AECs en CMECs, en nekrose te inhibeer in AECs. In die ex vivo model van besering, het aortaringe van 16-week HFD rotte ‘n pro-kontraktiele respons tot fenielefrien-geïnduseerde kontraksie getoon, wat deur OA omgekeer is. Ten slotte, nuwe bevindinge is waargeneem m.b.t. endoteel-heterogeniteit tussen AECs en CMECs onder basislyn en TNF-α-behandelde omstandighede. Alhoewel verlaagde NO-biobeskikbaarheid die waarmerk van endoteeldisfunksie is, het hierdie studie getoon dat seintransduksiepaaie wat endoteelbesering medieer verskillend is tussen seltipes. Die studie het verder ook gedemonstreer dat OA beskermende eienskappe toon in AECs en CMECs, ‘n waarneming wat ook in die ex vivo model aangetoon kon word.
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Anglin, Sandra Sophia Charmain. "The role of the local renin-angiotensin system in the development of fibrocellular intimal hyperplasia following balloon catheter-induced injury in the rat". Thesis, Imperial College London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307441.
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Flynn, Paul Desmond. "Transgenic rats expressing apolipoprotein(a) : generation, characterisation and response to vascular injury". Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621943.
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Baker, R. C. "Modulation of peri-operative renal injury in a model of vascular surgery". Thesis, Queen's University Belfast, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.396890.
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Armstrong, Johanna. "C-fos, response to injury and local drug delivery in vascular models". Thesis, University of Sheffield, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312781.
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Mitchell, Andrew Joseph. "Understanding the role of endothelial progenitor cells in vascular injury and repair". Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33310.
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Introduction: Vascular injury is the crucial initiating event in atherosclerosis and is universal following percutaneous coronary intervention. The cellular response to this injury largely determines vessel outcome. Endothelial progenitor cells (EPCs) and their progeny, late outgrowth endothelial cells (EOCs) are thought to play an important role in this process and characterising this role would be valuable in better understanding vascular injury and repair. Methods: The radial artery in the context of transradial cardiac catheterisation was examined as a model of vascular injury with characterisation of structural injury, longitudinal function and EPC populations. To examine the role of late outgrowth endothelial cells a method for GMP-compliant cell culture and labelling with F18Fluorodeoxyglucose was developed with a view to conducting a cell-tracking study of human administration. Results: Radial artery function was reduced following transradial cardiac catheterisation with recovery over a period of three months. There was no correlation between recovery of arterial function and EPC populations as defined by conventional surface markers. A research grade protocol for EOC culture was successfully translated to a GMP-compliant process producing a viable, phenotypically homogeneous EOC product. Cells were successfully labelled with F18Fluorodeoxyglucose and whilst proliferation was reduced, acute viability and function were not compromised. Conclusion: The radial artery in the context of transradial cardiac catheterisation is a useful model of vascular injury and repair although recovery of vascular function does not appear to be influenced by EPC populations. GMP-compliant culture and labelling of EOCs is feasible and will allow examination of the physiology of these cells in vivo in man.
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Dawoud, Hazem Elsaid. "Nanomedical Studies of Angiographic Contrast-Induced Renal and Vascular Injury: Clinical Implications". Ohio University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1522677857523823.
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Ammann, Kaitlyn R., Katrina J. DeCook, Phat L. Tran, Valerie M. Merkle, Pak K. Wong i Marvin J. Slepian. "Collective cell migration of smooth muscle and endothelial cells: impact of injury versus non-injury stimuli". BioMed Central, 2015. http://hdl.handle.net/10150/610313.
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BACKGROUND: Cell migration is a vital process for growth and repair. In vitro migration assays, utilized to study cell migration, often rely on physical scraping of a cell monolayer to induce cell migration. The physical act of scrape injury results in numerous factors stimulating cell migration - some injury-related, some solely due to gap creation and loss of contact inhibition. Eliminating the effects of cell injury would be useful to examine the relative contribution of injury versus other mechanisms to cell migration. Cell exclusion assays can tease out the effects of injury and have become a new avenue for migration studies. Here, we developed two simple non-injury techniques for cell exclusion: 1) a Pyrex® cylinder - for outward migration of cells and 2) a polydimethylsiloxane (PDMS) insert - for inward migration of cells. Utilizing these assays smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs) migratory behavior was studied on both polystyrene and gelatin-coated surfaces. RESULTS: Differences in migratory behavior could be detected for both smooth muscle cells (SMCs) and endothelial cells (ECs) when utilizing injury versus non-injury assays. SMCs migrated faster than HUVECs when stimulated by injury in the scrape wound assay, with rates of 1.26 % per hour and 1.59 % per hour on polystyrene and gelatin surfaces, respectively. The fastest overall migration took place with HUVECs on a gelatin-coated surface, with the in-growth assay, at a rate of 2.05 % per hour. The slowest migration occurred with the same conditions but on a polystyrene surface at a rate of 0.33 % per hour. CONCLUSION: For SMCs, injury is a dominating factor in migration when compared to the two cell exclusion assays, regardless of the surface tested: polystyrene or gelatin. In contrast, the migrating surface, namely gelatin, was a dominating factor for HUVEC migration, providing an increase in cell migration over the polystyrene surface. Overall, the cell exclusion assays - the in-growth and out-growth assays, provide a means to determine pure migratory behavior of cells in comparison to migration confounded by cell wounding and injury.
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Zargham, Ramin. "[Alpha]8[beta]1 integrin and vascular injury : role of [alpha]8[beta]1 integrin in restenosis after balloon injury". Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111876.
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Restenosis is the major cause of the failure of reconstruction methods to restore the blood flow in atherosclerotic arteries. Restenosis results from neointima formation and consequent constrictive remodelling. Vascular smooth muscle cell (VSMC) migration from the tunica media toward the intima is crucial in neointima genesis. The prerequisite for VSMC migratory activity is the modulation from the differentiated (contractile) to the de-differentiated (noncontractile) phenotype. VSMC phenotype change is associated with the altered expression of integrins. alpha8beta1 integrin is upregulated in cell types with contractile properties, including myofibroblasts and mesangial kidney cells. It is one of the integrins that is intensely expressed in mature VSMCs. alpha8beta1 integrin expression during vascular injury and its role in VSMC function have not been studied so far.In this work, a rat model of carotid angioplasty was used to mimic vascular injury in humans. alpha8beta1 integrin was downregulated in the tunica media concomitantly with loss of the contractile phenotype. In vitro study revealed that it is a differentiation marker of VSMCs. To test the functional significance of the association between alpha8 integrin and the VSMC phenotype, short interference RNA was deployed to silence the alpha8 integrin gene. alpha8 integrin gene silencing heightened VSMC migratory activity as well as modulation of the VSMC phenotype in favour of the noncontractile state. In addition, alpha8 integrin overexpression induced re-differentiation of VSMCs and attenuated their migratory activity. It is, therefore, suggested that alpha8 integrin overexpression after vascular injury might control VSMC migration and neointima formation. On the other hand, alpha8 integrin gene silencing led to a reduced growth rate, which indicated a dichotomy between VSMC migration and proliferation.
In the later stages of neointima formation, constrictive remodeling plays a major role in late lumen loss. Our data demonstrated that alpha8 integrin is upregulated in the neointima during constrictive remodeling with concomitant luminal narrowing. The importance of this finding was highlighted by results showing that alpha8 integrin was required for the VSMC contractile phenotype evoked by transforming growth factor-beta (TFG-beta) and TFG-beta-induced myofibroblastic differentiation of Rat1 fibroblasts. Thus, it appears that alpha8 integrin expression blockade might reduce contractile remodeling and late lumen loss. Although the mechanism of alpha8 integrin signaling is not yet clear, our findings demonstrate that the alpha8 integrin-induced contractile phenotype is blocked by RhoA inhibitors. Furthermore, alpha8 integrin and RhoA are co-immunoprecipitated, and alpha8 integrin gene silencing reduces RhoA activity. Hence, it is postulated that alpha8-RhoA signaling might be closely intertwined.
Altogether, these studies indicate that alpha8 integrin is a contractile marker of VSMCs and a negative regulator of VSMC migration. Therefore, forced alpha8 integrin expression may be applied to reduce neointima formation. However, alpha8 integrin upregulation during constrictive remodeling concomitant with late lumen loss suggest that it could be involved in lumen narrowing. It seems likely that in therapeutic strategies to reduce restenosis the timeline of interference might be very important. Therefore, alpha8 integrin gene silencing in the later stages of neointima formation might be beneficial.
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Partridge, Charles Randal. "Identification and molecular characterization of novel genomic targets in oxidant-induced vascular injury". Diss., Texas A&M University, 2005. http://hdl.handle.net/1969.1/5024.
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Gene expression was examined in vascular smooth muscle cells to study the complex interaction between oxidative injury and the pathogenesis of vascular disease. Extensive vascular remodeling coupled to increased production of 8-epi-PGF2ñ nuclear localization of NFúB, and alterations in glutathione homeostasis were identified as major responses of the vascular wall to oxidative stress. Transcriptional profiling studies, supported by immunohistochemistry and in situ hybridization measurements, identified genes involved in adhesion and extracellular matrix deposition (ñ1 integrin, collagen), cytoskeletal rearrangements (ñ-smooth muscle actin, ñ-tropomyosin), and signal transduction (NFúB, osteopontin, and LINE) as targets of oxidant injury. In the case of osteopontin (OPN), elevation of OPN levels in vSMCs was shown to be mediated by redox-regulated transcriptional mechanisms. A 200bp region located in the 5' UTR of the osteopontin promoter was found to be responsive to oxidative stress. This regulatory region contained two distinct cis acting elements involved in promoter inducibility. These elements were tentatively identified as NFKB and TIEG-1 binding sites and shown to be highly responsive to hydrogen peroxide and chemical antioxidants. Collectively these studies answer central questions regarding the mechanisms underlying the vascular response to oxidative stress and the involvement of OPN in diseases of the vascular wall.
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Chen, Q. "Role of natriuretic peptides in the response of vascular smooth muscle to injury". Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597554.
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Vascular smooth muscle cell (VSMC) proliferation with neointima formation is the key feature of restenosis after successful percutaneous transluminal coronary angioplasty (PTCA), which severely limits the clinical benefits of a major option in the treatment of coronary heart disease. To date, the prevention and therapy of restenosis in humans remain limited or unsuccessful. Natriuretic peptides (NP) are powerful inhibitors of VSMC proliferation in vitro. However, the mechanisms by which NP inhibit VSMC proliferation are still nuclear, and neither are the in vivo effects of NP on VSMC proliferation known. This dissertation is addressed to the study of the interaction of the NP system with VSMC under pathological conditions of arterial injury. Normal VSMC from different species or different arteries all expressed NP receptors (NPR), although in different subtypes. Normal rat carotid arteries expressed type-A NPR (NPR-A), whereas normal rabbit ear central arteries expressed exclusively type-B NPR (NPR-B). Despite this difference in normal arteries, neointimal VSMC in both rat and rabbit arteries expressed the same subtype of NPR, type-C (NPR-C) implying the involvement of NPR-C in the regulation of arterial response to injury. In the rabbit model of arterial injury, the media of damaged arteries also expressed NPR-C besides the NPR-B that already exists in normal arteries. Time course experiments of NPR expression in this model showed that NPR-C were upregulated between 5 and 7 days after arterial injury. Affinity cross-linking demonstrated that the molecular weights of reduced NPR-A, NPR-B and NPR-C in arteries were 120, 130 and 64 kDa, respectively. Second messenger assays showed that NPR-A and NPR-B in the normal arteries were coupled with cGMP system, whereas NPR-C was not found to be coupled to the cGMP nor to the cAMP system.
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Liu, Zhi Zhao [Verfasser]. "Renal vascular function and contrast media induced acute kidney injury / Zhi Zhao Liu". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2013. http://d-nb.info/1042657602/34.
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Ellison, Stephen Patrick. "THE EFFECTS OF INTERLEUKIN-19 ON ATTENUATION OF THE VASCULAR RESPONSE TO INJURY". Diss., Temple University Libraries, 2015. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/253270.
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PhysiologyPh.D.
BACKGROUND: Despite aggressive dietary modification, lipid lowering medications, and other medical therapy, vascular proliferative diseases continue to account for 50% of all mortality in the United States. It is a significant medical and socioeconomic problem contributing to the mortality of multiple diseases including myocardial infarction (MI), stroke, renal failure, and peripheral vascular disease. With a growing number of children becoming obese and an increase in the number of patients with co-morbidities such as metabolic syndrome and Type 2 diabetes mellitus, epidemiological studies project the morbidity and mortality of these diseases to increase. Among these vascular proliferative diseases are primary atherosclerosis, vascular restenosis, and allograft vasculopathy, all of which are the result of chronic inflammation believed to stem from initial endothelial injury. Once activated by any number of potential injurious agents, endothelial cells (ECs) secrete cytokines that act on multiple cell types. Stimulation of resident vascular smooth muscle cells (VSMCs) results in a phenotypic switch from a normally contractile state to a proliferative state. Following this phenotypic shift, VSMCs migrate from the media to the intima of the artery where they begin secretion of both pro- and anti-inflammatory cytokines. Vascular proliferative disease ensues as a result of the autocrine and paracrine signaling of these cytokines between many different cell types including ECs, VSMCs, macrophages, and T-cells. As a result of the integral role pro- and anti-inflammatory cytokines play in the development of vascular proliferative diseases, they have become the subject of intense study in the field of cardiovascular research. Interleukin-19 (IL-19) is a newly described member of the IL-10 sub-family of anti-inflammatory cytokines. Discovered in 2000, it was originally only thought to be basally expressed in monocytes and lymphocytes, however in 2005 our lab discovered that while uninjured arteries have no detectable IL-19, arteries of patients with vascular proliferative diseases have notable IL-19 expression. Since its discovery in multiple cell types of injured arteries, our lab has subsequently shown that IL-19 inhibits proliferation, migration, spreading, production of reactive oxygen species (ROSs), and expression of pro-inflammatory genes in VSMCs, while in ECs IL-19 has been shown to promote angiogenesis, proliferation, migration, and spreading. AIMS and HYPOTHESIS: The first aim of the current study is to show that IL-19 is expressed in atherosclerotic plaque, and to test that IL-19 can reduce experimental atherosclerosis in susceptible mice. The second aim of the study is to show that IL-19 can regulate development of intimal hyperplasia in a murine model of restenosis. For both aims, we sought to identify potential intracellular signaling mechanisms of IL-19 which produce the observed effect. These aims directed our overall hypothesis that the anti-inflammatory properties of IL-19 can attenuate the vascular response to injury in various animal models of vascular proliferative disease. METHODS and RESULTS: The first aim of this dissertation showed that LDLR-/- mice fed an atherogenic diet and injected with either 1.0ng/g/day or 10.0ng/g/day rmIL-19 had significantly less plaque area in the aortic arch compared with controls (p<0.0001). Weight gain and serum lipid levels were not significantly different. IL-19 could halt, but not reverse expansion of existing plaque. Gene expression in splenocytes from IL-19 treated mice demonstrated immune cell Th2 polarization, with decreased expression of T-bet, IFNgamma, IL-1β and IL-12β, and increased expression of GATA3 messenger ribonucleic acid (mRNA). A greater percentage of lymphocytes were Th2 polarized in IL-19 treated mice. Cellular characterization of plaque by immunohistochemistry demonstrated IL-19 treated mice have significantly less macrophage infiltrate compared with controls (p<0.001). Intravital microscopy revealed significantly less leukocyte adhesion in wild-type mice injected with IL-19 and fed an atherogenic diet compared with controls. Treatment of cultured EC, VSMC, and bone marrow-derived macrophages (BMDM) with IL-19 resulted in a significant decrease in chemokine mRNA, and in the mRNA-stability protein HuR. In the second aim of this dissertation we showed that IL-19 attenuates vascular restenosis in response to carotid artery ligation. Carotid artery ligation of hyper-responsive friend leukemia virus B (FVB) wild-type mice injected with 10ng/g/day rIL-19 had significantly lower neointima/media ratio (I/M) compared with phosphate buffered saline (PBS) controls (p=0.006). Conversely, carotid artery of IL-19-/- mice demonstrated significantly higher I/M ratio compared with wild-type mice (p=0.04). Importantly, the increased I/M ratio in the knockout mice could be rescued by injection of 10ng/g/day IL-19 (p=0.04). VSMC explanted from IL-19-/- mice proliferated significantly more rapidly compared with wild-type (p=0.04). Surprisingly, in this model, IL-19 does not modulate adoptive immunity. Rather, addition of IL-19 to cultured wild-type VSMC did not significantly decrease VSMC proliferation, but could rescue proliferation in IL-19-/- VSMC to wild-type levels (p=0.02). IL-19-/- VSMC expressed significantly greater levels of inflammatory mRNA including IL-1β, TNFα, and MCP-1 in response to TNFα stimulation (p<0.01 for all). No polarization of adaptive immunity was noted in these mice. CONCLUSIONS: These data are the first to report that IL-19 is a potent inhibitor of experimental atherosclerosis via diverse mechanisms including immune cell polarization, decrease in macrophage adhesion, and decrease in gene expression. In addition, these data are also the first to show that IL-19 plays a previously unrecognized protective role in vascular restenosis. Together, these data suggest IL-19 is both anti-atherogenic and anti-restenotic and may identify IL-19 as a novel therapeutic to limit vascular inflammation.
Temple University--Theses
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Ohashi, Naohiro. "Role of p38 Mitogen-Activated Protein Kinase in Neointimal Hyperplasia After Vascular Injury". Kyoto University, 2001. http://hdl.handle.net/2433/150561.
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Sayers, Rebecca Lynn Taylor Joan M. "Focal adhesion kinase and its endogenous inhibitor, FRNK, in vascular development and injury". Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,2089.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Feb. 17, 2009). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Cell and Molecular Physiology." Discipline: Cell and Molecular Physiology; Department/School: Medicine.
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Ali, Ziad A. "Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in the response to vascular injury". Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437385.
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Robinson, Hollie Christine. "Investigation of the role of microRNA-143 and microRNA-145 in acute vascular injury". Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5221/.
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Vascular smooth muscle cell (VSMC) activation leading to proliferation, migration and extracellular matrix (ECM) production is a major cause of neointimal formation after stenting and coronary artery bypass grafting. Drug-eluting stents have reduced clinical incidence of in-stent restenosis by inhibiting this proliferative response but they can also delay vessel re-endothelialisation after injury leading to an increased thrombotic risk. MicroRNAs (miRNAs) are short (~22 nt) non-protein-coding RNAs which act as regulators of gene expression largely through binding to the 3’ untranslated region of target genes and causing degradation or repression of expression. MiR-143 and miR-145 are a miRNA family that are enriched in VSMCs and have been previously shown to influence VSMC phenotype through regulation of their gene targets. Consequently, the aim of this study was to investigate the role that miR-143 and miR-145 play in the neointimal response to stenting. Initial experiments investigated whether modulation of miR-143 or miR-145 expression was capable of significantly altering VSMC phenotype. It was found that modulation of miRNA levels in human saphenous vein (HSV) SMC or endothelial cells (EC) using adenoviruses was not ideal due to transduction and toxicity issues. Use of antimiR miRNA inhibitors and premiR miRNA mimics revealed that modulation of miR-143 or miR-145 levels alone was not sufficient to alter proliferation or migration of HSV SMCs in vitro. Knockdown of miR-143 expression in cells resulted in de-repression of target genes kruppel-like factor 4 (KLF4) and KLF5 but expression levels of other previously identified target genes were unaltered by miRNA modulation. Pre-clinical stenting studies are largely performed in porcine models due to similarities in vessel structure and neointimal formation, however large animal models are not ideal for early investigative studies. In order to examine the role of miR-143 and miR-145 in stent-induced vascular injury we utilised a mouse model where a bare metal stent is deployed in the thoracic aorta of a donor mouse and interposition grafted into the carotid artery of a recipient. This model resulted in the development of a defined neointima over 28 days which consisted largely of VSMCs and ECM, similar to that of the human in-stent restenosis. Vessel expression of miR-143 and miR-145 has been previously shown to be reduced following vascular injury and furthermore overexpression of these miRNA can reduce neointimal formation. MiR-143 and miR-145 knockout (KO) mice have previously been shown to have abnormal VSMC phenotype in their vessel walls including perturbed stress fiber formation, increased presence synthetic machinery and an increased number of synthetic versus contractile VSMCs. MiR-143 and miR-145 KO mice were found to develop significantly less neointimal formation in response to stenting than WT mice indicating that these miRNA are essential for normal vessel response to injury. The reduced neointimal formation following genetic ablation of miR-143 or miR-145 led to the investigation of whether pharmacological knockdown of these miRNA was able to mimic this effect. An antimiR consisting of DNA and locked nucleic acid bases targeted against mature miR-143 expression was used to knockdown miR-143 expression in mice prior to stenting. AntimiR-143-mediated knockdown of miR-143 expression did not significantly alter the degree of neointimal formation seen 28 days following stent deployment when compared to mice that received a control non-targeted antimiR (antimiR-ctl). The neointima of both antimiR-143 and antimiR-ctl mice were comparable and consisted largely of VSMCs and ECM. Re-endothelialisation had occurred by day 28 post-injury in antimiR-143 and antimiR-ctl treated mice indicating that knockdown of miR-143 did not significantly delay EC repopulation in this model. Expression of miRNA and mRNA after vascular injury can be both spatial and temporal. Target de-repression was not detected in the aorta or heart of miRNA KO or antimiR-143 treated mice. This is likely to reflect the complex nature of miRNA gene regulation in vivo which is governed by many different factors including the relative expression of the miRNA and its target, cell stress, and transcriptional activation or inhibition by growth and transcription factors. In summary, the influence of miR-143 and miR-145 on VSMC biology was investigated in vitro using a range of molecular biology techniques and in vivo in a mouse model of in-stent stenosis. Results have extended current knowledge of the degree of influence these miRNA exert over VSMC phenotype and identified that miR-143 and miR-145 are involved in neointimal formation after stenting.
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Low, Emma Louise. "Dissecting transforming growth factor-beta signalling pathways in the context of acute vascular injury". Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/30703/.
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Coronary artery bypass grafting (CABG) is a mainstay in the treatment of coronary heart disease (CHD), a leading cause of premature death in the UK. However, fewer than 60 % of saphenous vein grafts remain patent in the long-term due to the formation of a hyperplastic, occlusive neointima within the grafted vessel. Excessive vascular smooth muscle cell (VSMC) proliferation, migration and extracellular matrix (ECM) synthesis are key events in the pathogenesis of vein graft intimal hyperplasia (IH), and subsequent necrotic core formation and intraplaque haemorrhage further accelerate the process of vein graft failure by forming unstable atherosclerotic lesions. Early IH therefore represents an important target for therapeutic interventions aimed at improving clinical outcomes after CABG. The pleiotropic cytokine transforming growth factor-beta (TGFβ) is highly expressed in restenotic vessels from CHD patients and is acutely upregulated following vein graft implantation in large and small animal models of vein graft disease. To date, most studies investigating the role of TGFβ in IH have used global approaches to target TGFβ, or have focused on the canonical activin receptor-like kinase 5 (ALK5), Smad2/3-mediated pathway. However, TGFβ elicits a diverse range of cellular responses by activating several distinct signalling pathways, and in certain cell types can also signal via ALK1, activating a separate set of receptor-regulated Smad proteins (R-Smads; Smad1/5) that can antagonise ALK5 signalling. Importantly, the role of ALK1 in the pathogenesis of vein graft IH remains unclear and studies have yet to conclusively show whether TGFβ is able to signal via ALK1 in VSMCs. Moreover, in vivo studies indicate that the three mammalian TGFβ isoforms have discrete biological functions, especially during wound healing, a process similar to IH involving cell migration, proliferation and ECM formation. Therefore, the principal aim of this thesis was to dissect the roles of ALK5- and ALK1-mediated signalling in VSMCs during vein graft IH. In addition, this thesis aimed to evaluate whether TGFβ1, TGFβ2 and TGFβ3 differentially regulate VSMC behaviour in the context of vein graft IH. Initially, the expression of the TGFβ isoforms, ALK receptors and R-Smads in VSMCs during the development of IH was evaluated in both small and large animal models of arterial injury and vein graft disease. IHC analysis of wire-injured mouse carotid arteries 14 days post-injury revealed that TGFβ1, TGFβ3, ALK5 and ALK1 were expressed in αSMA+ intimal and medial VSMCs. Interestingly, while nuclear localisation of phosphorylated Smad2/3 (pSmad2/3) within αSMA+ VSMCs was observed in both non-injured and injured vessels, nuclear pSmad1/5 was only detected within VSMCs following vascular injury. IHC analysis of TGFβ signalling components in diseased pre-implantation human saphenous vein (HSV) with pre-existing IH showed that TGFβ1, TGFβ3, TβRII (TGFβ type II receptor), ALK5 and ALK1 were expressed in αSMA+ VSMCs within both the intima and media. Importantly, dual staining for TβRII and ALK5 or ALK1 showed strong co-localisation between ALK5/ALK1 and TβRII. Both pSmad2/3 and pSmad1/5 were localised to the nuclei of intimal αSMA+ VSMCs, suggesting that both ALK5 and ALK1 signalling pathways may be active in these cells. Confocal microscopy analysis of three failed vein graft specimens obtained from patients undergoing cardiac transplantation revealed abundant nuclear-localised pSmad2/3 and pSmad1/5 in αSMA+ intimal VSMCs. These data suggest that both the ALK5 and ALK1 pathways may be activated in VSMCs during the development of IH. Having localised TGFβ1, TGFβ3, TβRII, ALK5, ALK1, pSmad2/3 and pSmad1/5 to intimal vein graft SMCs, subsequent mechanistic characterisation of TGFβ signalling via ALK5/ALK1 was performed in SMC outgrowth cultures from pre-implantation HSV segments from CABG patients (HSVSMC). Affinity labelling and crosslinking studies using 125I-TGFβ1 revealed binding of TGFβ1 to ALK5, ALK1 and TβRII, as well as the accessory receptors endoglin and betaglycan in HSVSMC. qRT-PCR confirmed the expression of these receptors at the RNA level, while immunoblotting revealed that treatment with all three TGFβ isoforms could induce a rapid increase in pSmad2 as well as pSmad1/5. Immunocytochemistry demonstrated the nuclear localisation of both pSmad2/3 and pSmad1/5 signalling complexes following stimulation of HSVSMC with TGFβ1, while qRT-PCR evaluation of ALK5 and ALK1 target genes (SERPINE1 and ID1, respectively) confirmed the transcriptional activation of both ALK signalling pathways by all three TGFβ isoforms. Importantly, pharmacological inhibition of ALK5 or ALK1 (using SB525334 or K02288, respectively) or siRNA-mediated knockdown of ALK5 or ALK1 in TGFβ-stimulated HSVSMC, reduced the expression of pSmad2 and pSmad1/5, respectively, confirming that TGFβ can bind to and signal through both ALK5 and ALK1 in HSVSMC. Functional assays performed in HSVSMCs indicated that TGFβ1, TGFβ2 and TGFβ3 regulate VSMC proliferation and migration in a similar manner in vitro. To gain insight into how the ALK5 and ALK1 TGFβ signalling pathways regulate VSMC proliferation, migration and apoptosis, functional assays were performed in HSVSMC treated with TGFβ1 ± SB525334 or K02288. Pharmacological inhibition of ALK5 or ALK1 did not significantly alter HSVSMC proliferation in response to TGFβ1. Interestingly, TGFβ1-mediated HSVSMC migration was significantly attenuated in the presence of ALK1 small molecule inhibitor, K02288, whereas inhibition of ALK5 signalling by SB525334 had no significant effect on HSVSMC migration. TGFβ1 protected from hydrogen peroxide-induced HSVSMC apoptosis and inhibition of ALK5 or ALK1 signalling reversed this effect. These studies indicate that TGFβ signalling via ALK5 and ALK1 differentially regulates HSVSMC migration, but not proliferation or apoptosis. Data output from the Human TGFβ/BMP RT2 Profiler PCR Arrays suggested that several TGFβ signalling pathway genes were differentially expressed following rTGFβ treatment in HSVSMCs, whereby some TGFβ isoform-specific effects on gene expression were observed. However, following validation, no TGFβ isoform-specific effects on gene expression were detected. Whole genome expression profiling of migrating HSVSMCs treated with TGFβ1 ± SB525334 or K02288 was performed in order to compare the gene expression profiles directly regulated by ALK5 and ALK1. In total, the expression of 3,235 genes was modulated by TGFβ1 treatment compared with non-stimulated HSVSMCs, approximately half of which appeared to be co-ordinately dysregulated following ALK5 and ALK1 inhibition. Two groups of putative ALK5- and ALK1-specific transcriptional targets were chosen for more detailed evaluation and validation. qRT-PCR validation in HSVSMC confirmed fibroblast growth factor 2 (FGF2) and Mal, T-cell differentiation protein like (MALL) as ALK5-specific target genes, and fatty acid desaturase 1 (FADS1), H1 histone family member 0 (H1F0) and scavenger receptor class A member 3 (SCARA3) as ALK1-specific target genes. Together, this data indicates that TGFβ regulates HSVSMC behaviour during the pathogenesis of vein graft IH by activating distinct, ALK receptor-specific transcriptional networks. Overall, the findings from this thesis indicate that the ALK1/Smad1/5 TGFβ signalling pathway is activated following vascular injury and induces specific transcriptional changes to promote VSMC migration. Moreover, these studies indicate that TGFβ1, TGFβ2 and TGFβ3 regulate VSMC behaviour in a similar manner in vitro and all isoforms appear to have equivalent effects on the induction of established ALK5 and ALK1 target genes. Together, these findings highlight the potential of targeting non-canonical TGFβ signalling pathways in the setting of vein graft failure.
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Xu, Yang. "Role of bone marrow-derived progenitor cells in cuff-induced vascular injury in mice". Kyoto University, 2004. http://hdl.handle.net/2433/147517.
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Malabanan, Kristine Paz Centre for Vascular Research Faculty of Medicine UNSW. "Roles of activation transcription factor 4 (ATF4) and YrdC in the response of vascular smooth muscle cells to injury". Publisher:University of New South Wales. Centre for Vascular Research, 2008. http://handle.unsw.edu.au/1959.4/41338.
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Neointimal proliferation is a key process underlying many cardiovascular diseases such as atherosclerosis and angioplasty-induced restenosis. Vascular smooth muscle cells (SMC) are significant contributors to the development and stability of the neointimal lesion. This is due, in part, to their capacity to be phenotypically modulated, facilitating SMC proliferation in response to mechanical injury, their subsequent migration, and deposition of extracellular matrix. The aim of this thesis was to characterize the function of two genes identified in our laboratory to be upregulated shortly after mechanical injury of vascular SMC and their exposure to fibroblast growth factor (FGF)-2, an injury-induced cytokine. The first is activation transcription factor (ATF) 4, which is upregulated by FGF-2 and mechanical injury in vascular SMC in vitro, and by balloon-injury in the artery wall. The induction of ATF4 by FGF-2 was shown to be mediated through the PI3K pathway, and preceded by phoshorylation of eIF2alpha, a known upstream effector of ATF4 activation. Knock-down of ATF4 expression inhibited balloon-injury induced neointimal hyperplasia, suggesting that ATF4 is a key player in the SMC response to injury. Furthermore, microarray analysis identified several genes whose transcription in response to FGF-2 may be regulated by ATF4. In particular, this work demonstrates that ATF4 is necessary for VEGF-A upregulation in SMC in response to FGF-2 and mechanical injury in vitro and in the artery wall following balloon-injury. The second is a translation factor, YrdC203. Using confocal fluorescence microscopy, YrdC203 was found to localize partially to the ER, and with RPL12, a component of the 60S ribosomal subunit. Immunoprecipitation studies demonstrate that YrdC203 also interacts with an initiation factor, eIF5B. Mutation of an initiation factors signature on the exterior of YrdC203 perturbed its interaction with RPL12 and eIF5B, and inhibited the increase in protein synthesis observed with overexpression of YrdC203. This implicates YrdC203 as a translation factor responsible for ensuring protein synthesis in vascular SMC in response to injury. The present work provides evidence for new molecular mechanisms, transcriptional and translational, regulating the response of vascular SMC to injury. This would provide leads for future therapeutic targets.
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Carvalho, Maria Dulce Ribeiro. "In vitro studies of functional effects of antiendothelial cell autoantibodies". Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244285.
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Olby, Natasha J. "An experimental model of rat spinal cord injury : its development and studies on manipulation of its glial environment". Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243014.
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Pay, Salih, Meral Calguneri, Zafer Caliskaner, Ayhan Dinc, Sule Apras, Ihsan Ertenli, Sedat Kiraz i Veli Cobankara. "Evaluation of vascular injury with proinflammatory cytokines, thrombomodulin and fibronectin in patients with primary fibromyalgia". Nagoya University School of Medicine, 2000. http://hdl.handle.net/2237/5359.
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Brickler, Thomas Read. "The Role of Age and Model Severity on Cortical Vascular Response Following Traumatic Brain Injury". Diss., Virginia Tech, 2017. http://hdl.handle.net/10919/85566.
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Traumatic brain injury (TBI) is a growing health concern worldwide that affects a broad range of the population. As TBI is the leading cause of disability and mortality in children, several pre-clinical models have been developed using rodents at a variety of different ages; however, key brain maturation events are overlooked that leave some age groups more or less vulnerable to injury. Thus, there has been a large emphasis on producing relevant animal models to elucidate molecular pathways that could be of therapeutic potential to help limit neuronal injury and improve behavioral outcome. TBI involves a host of different biochemical events, including disruption of the cerebral vasculature and breakdown of the blood brain barrier (BBB) that exacerbate secondary injuries. A better of understanding of the mechanism(s) underlying cerebral vascular regulation will aid in establishing more effective treatment strategies aimed at improving cerebral blood flow restoration and preventing further neuronal loss. Our studies reveal an age-at- injury dependence on the Angiopoetin-Tie2 axis, which mediates neuroprotection in a model of juvenile TBI following cortical controlled impact (CCI) that is not seen in adult mice. The protection observed was mediated, in part, by the microvascular response to CCI injury and prompted further detailed analysis of the larger arteriole network across several mouse strains and models of TBI. Our second study revealed both a model and species dependent effect on a specialized network of arteriole vessels, called collaterals after trauma. We demonstrated that a repetitive mild TBI (rmTBI) can induce collateral remodeling in C57BL/6 but not CD1 mice; however, CCI injury had no effect on collateral changes in either strain. Together, these findings demonstrate an age-dependent and species/model dependent effect on vascular remodeling that highlights the importance of individualized therapeutics to TBI.Ph. D.
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Stacy, Mitchel R. "The Effect of Eccentric Exercise-Induced Muscle Injury on Vascular Function and Muscle Blood Flow". University of Toledo / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1302229144.
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Ramachandra, Rakshit. "Injury and Impact Responses of the Abdomen Subjected to Seatbelt Loading". The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1480497361350603.
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Ashawesh, Mohamed. "Ultrasound enhanced gene delivery of secreted Interleukin 1 receptor antagonist in a murine vascular injury model". Thesis, University of Sheffield, 2017. http://etheses.whiterose.ac.uk/18481/.
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Ultrasound (US) mediated gene delivery (UMGD) is a non-viral technique for gene transfer that has been a developing technology over the past 18 years. Non-viral UMGD as an approach is safe, relatively cheap and can be tolerated even over multiple exposures. US exposure has previously been demonstrated to increase DNA transfer and expression in endothelial cells (EC) and vascular smooth muscle cells (VSMC) in vitro and ex vivo in a saphenous vein graft model. Interleukin-1 (IL-1) is a pro-inflammatory cytokine that plays a key role in cardiovascular diseases and vascular injury. Treatment with the endogenous inhibitor interleukin-1 receptor antagonist (IL-1Ra) is an effective treatment in animal models of vascular disease and some inflammatory clinical conditions. However, Anakinra (the clinically approved formulation of IL-1Ra) must be given as daily subcutaneous (SC) injections (due to a short t ½), which is inconvenient (high burden for compliance) and very expensive. In this project I have tested US parameters for ‘best’ gene expression in the mouse hind limb, demonstrated long-term expression utilising a repeat dosing regime and finally investigated the therapeutic efficacy of intramuscular (IM) UMGD of pCMV6-SIL1Ra in a rodent arterial injury model compared with continuous delivery of Anakinra via osmotic mini-pump. Following experiments to determine the US dose, duration of expression and therefore treatment schedule, I have demonstrated that this new UMGD technique of pCMV6-SIL1Ra, every 4 days over a period of 28 days significantly decreased neointima/media (N/M) ratio in a murine vascular injury model. Furthermore, there was no significant difference between mice treated with pCMV6-SIL1Ra-UMGD and those receiving continuous Anakinra infusion by osmotic mini-pump (25 mg/kg/), suggesting that UMGD was at least as efficacious as drug treatment in reducing neointima formation. The role of IL-1 in neointima formation following vascular injury is not new but these novel data demonstrate the potential for UMGD to achieve therapeutic levels of gene/protein expression in an animal model and highlight the potential for further development. This technique of UMGD utilising a secreted protein and easily accessible muscle tissue from which to express it warrants further investigation as a possible treatment for other cardiovascular and systemic/peripheral diseases where a secreted protein is an attractive drug treatment.
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Kobuke, Kazuhiro. "ESDN, A Novel Neuropilin-like Membrane Protein Cloned from Vascular Cells with the Longest Secretory Signal Sequence among Eukaryotes, Is Up-regulated after Vascular Injury". Kyoto University, 2002. http://hdl.handle.net/2433/150206.
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Seeger, Joost. "Ischaemic preconditioning in exercise and disease : one size fits all?" Thesis, Liverpool John Moores University, 2016. http://researchonline.ljmu.ac.uk/4550/.
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Ischaemia reperfusion injury (IR-injury) occurs when blood supply to a certain area of the body is blocked, and is subsequently followed by reperfusion. During the period of ischaemia, tissue is damaged as a result of lack of oxygen. Rapid reperfusion is mandatory, but unfortunately causes damage in addition to the damage induced by ischaemia alone. While a prolonged period of ischaemia is harmful to the bodily tissue, short periods of ischaemia interspersed with short bouts of reperfusion have protective effects. This mechanism is called ischaemic preconditioning (IPC). In this thesis, the impact of co-morbidity and age on IR-injury and IPC are explored. Moreover, the possible role of IPC to enhance exercise performance is investigated. Finally an attempt is made to understand the interchangeable effects of IPC and exercise performance in the prevention of IR-injury. Using the brachial artery endothelial function as a surrogate marker, first the consequences of IR-injury in both young and older individuals on endothelial function were studied. It was also assessed whether IPC could prevent endothelial IR-injury. It was found that endothelial function in both groups declined, when IR-injury was not preceded with IPC. However, when IPC was applied prior to IR-injury, a protective effect was detected in young subjects, but not in older participants. In chapter 5, this study was repeated in patients with heart failure, as they are at an increased risk for IR-injury. While in both groups a significant decline in endothelial function was observed, a much larger decline was established in the heart failure group. Moreover, IPC failed to protect against endothelial dysfunction in heart failure patients after IR-injury. The third study presented in this thesis, focused on the question whether exercise performance enhancement during a 5-km time trial was comparable when IPC on the upper legs was applied immediately before the time trial versus 24 hours (24-IPC) prior to exercise. Interestingly, a significant and strong correlation was found in finish time between acute IPC and 24-IPC, suggesting comparable effects of IPC and 24-IPC on exercise performance. In a follow-up study, it was determined whether local IPC applied on the upper arm, or remote IPC applied on the legs, would lead to an improved maximum incremental arm crank exercise test in individuals with a complete spinal cord lesion. The main finding was that upper arm IPC led to an increased performance enhancement, whilst remote IPC (stimulus below the lesion) did not lead to any significant differences. These studies help to inform the best or most practical application of IPC in daily life situations. Some previous work has suggested that exercise may resemble some of the effects of IPC. More specifically, acute exercise might possess the same protective effects against ischaemia-reperfusion injury as IPC. Therefore, in young healthy individuals it was studied, whether an acute bout of endurance or interval exercise is able to protect against brachial endothelial IR-injury. It was established that interval exercise prevented endothelial dysfunction after an IR stimulus, while no protective effect of endurance exercise was found. It was concluded that interval exercise, but not endurance exercise, prevented endothelial dysfunction after an ischaemic period. In conclusion, this thesis provides further evidence for the protective effects of (remote) IPC, both on the prevention of endothelial IR-injury as well as improvement in exercise performance. However, effects may depend on the protocol and population studied.
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Pereira, Aline Carvalho. "Mecanismos celulares que influenciam a sinalização por receptores 1-adrenérgicos na carótida contra-lateral à lesão por cateter balão". Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/60/60138/tde-20102009-132757/.
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PEREIRA, A.C. Mecanismos celulares que influenciam a sinalização por 1-adrenoceptores na carótida contra-lateral à lesão por cateter balão. 2009. 127 f. Tese (Doutorado) - Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, 2009. Em artérias carótidas de ratos, a lesão provocada pela angioplastia por cateter balão resulta em resposta neurocompensatória na carótida contra-lateral à lesão, com aumento da inervação contendo substância P e CGRP (peptídeo relacionado ao gene da calcitonina), além de alteração de reatividade a agonistas vasoconstritores. O objetivo deste trabalho foi estudar os mecanismos relacionados à alteração de reatividade à fenilefrina (Phe) na carótida contra-lateral à lesão, 1, 2, 4 e 15 dias após a lesão. A análise histológica mostrou que a carótida contra-lateral à lesão é semelhante ao controle. Na artéria ipsi-lateral a camada endotelial estava ausente e, aos 15 dias após a lesão observou-se a presença da neoíntima. Curvas concentração-resposta para Phe (contração) foram realizadas em anéis isolados de carótidas contra-laterais e controles, 1, 2, 4 e 15 dias após a lesão. No quarto dia após a lesão, observou-se aumento no efeito máximo (Emax) da Phe na artéria contralateral em relação ao controle. Para avaliar se o aumento no Emax da Phe estava relacionado à mobilização de cálcio induzida por esse agonista, foi usada solução de Krebs sem cálcio, contendo ou não EGTA e curvas concentração resposta para CaCl2. Observamos que a mobilização de cálcio intracelular induzido pela Phe na contra-lateral não estava alterada em relação ao controle, mas o influxo de cálcio estava reduzido. Este resultado foi confirmado em usando anéis de carótida marcados com Fluo-3AM em microscópio confocal. Na presença de inibidores específicos, observou-se que a isoforma endotelial da enzima óxido nítrico sintase, canais para potássio dependentes de cálcio, prostanóides derivados da COX-2, ânion superóxido e junções do tipo Gap estão envolvidos na redução do influxo de cálcio na contra-lateral. No entanto, não há participação de óxido nítrico, guanilato ciclase ou da Ca-ATPase do retículo. Ânion superóxido, COX-2 e junções do tipo Gap também participam do aumento de Emax da Phe na carótida contra-lateral à lesão. Os resultados sugerem ainda que ânions superóxido promovem aumento da atividade de Rho-kinase na artéria contra-lateral em relação ao controle, conforme observado em curvas de relaxamento com Y-27632 (inibidor de Rho-quinase), após pré-contração com Phe. A potência para Phe e para CaCl2 na contra-lateral foi semelhante ao controle, assim como o relaxamento induzido pela acetilcolina e a contração desencadeada pelo KCl. Os resultados obtidos neste trabalho indicam que a resposta neurocompensatória ao cateter balão resulta em alterações na sinalização celular que interferem na reatividade à Phe na carótida contra-lateral à lesão. Estas alterações são dependentes do endotélio, desencadeadas, provavelmente, por um estresse oxidativo causado por ânions superóxido e sugerem a existência de mecanismos compensatórios para manter o tônus vascular.In rat carotid arteries, balloon catheter injury results in neurocompensatory response in contralateral carotid, leading to increased levels of substance P and CGRP (calcitonin gene-related peptide), beside alterations in reactiveness to vasoconstrictor agonists. The aim of this work was to study the mechanisms involved in alterations in phenylephrine (Phe) responsiveness in contralateral carotid, 1, 2, 4 and 15 days after injury. Histological analysis showed that contralateral carotid was similar to control. Endothelium was absent in ipsilateral arteries, but 15 days after lesion it was observed the neointima. Concentration-response curves to Phe (contraction) were performed in isolated carotid rings, control and contralateral, 1, 2, 4 and 15 days after lesion. In the fourth day after lesion, it was observed increase in maximum effect (Emax) to Phe in contralateral compared to control arteries. In order to verify if the increase in Emax to Phe was related to calcium mobilization by this agonist, it was used free-calcium Krebs solution containing or not EGTA, and concentration-response curves to CaCl2. It was observed that intracellular calcium mobilization by Phe was similar to control, but calcium influx was reduced in contralateral. Confocal microscopy, using carotid rings loaded with Fluo-3AM, was also utilized to corroborate this result. In presence of specific inhibitors, it was observed that endothelial isoform of nitric oxide synthase, calcium-activated potassium channels, prostanoids from COX-2, superoxide anions and Gap-junctions are involved on reduction of Phe-induced calcium influx. However, neither nitric oxide, guanylate cyclase nor sarcoendoplasmic reticulum Ca-ATPase participate in this response. Superoxide anions, COX-2 and Gap-junctions also play a role on increased Emax to Phe in contralateral carotid. Futhermore, superoxide anions promote increase in Rho-kinase activity in contralateral carotid compared to control, as it was observed in relaxation curves with Y-27632 (Rho-kinase inhibitor), after Phe pre-contraction. Phe and CaCl2 potency in contralateral were similar to control, like acetylcholine relaxation and KCl-induced contraction. Results obtained in this work indicate that the neurocompensatory response to balloon catheter injury leads to alterations in the signaling pathway downstream alpha1-adrenoceptor activation in contralateral carotid. These alterations are endothelium dependent and, probably, triggered by oxidative stress due to superoxide anions. Taken together, data suggest the existence of compensatory mechanisms to maintain the vascular tonus.
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Young, Yun Wai. "Pro-inflammatory growth factors reduce secondary degeneration after traumatic spinal cord injury". Thesis, Queensland University of Technology, 2013. https://eprints.qut.edu.au/60875/1/Yun%20Wai_Young_Thesis.pdf.
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The role of inflammatory response after spinal cord injury remains unclear. This thesis was a step forward in studying how promoting the inflammation, by delivery pro-inflammatory growth factors, affects the outcomes of spinal cord injury. A significant functional improvement was observed after treatment and these results suggest an interesting avenue for future clinical treatments and may provide a platform to improve the efficacy of other treatments.