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Journal articles on the topic 'Intraplaque angiogenesi'

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Published: 9 March 2023
Last updated: 10 March 2023

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1

Parma, Laura, Hendrika A. B. Peters, Fabiana Baganha, Judith C. Sluimer, Margreet R. de Vries, and Paul H. A. Quax. "Prolonged Hyperoxygenation Treatment Improves Vein Graft Patency and Decreases Macrophage Content in Atherosclerotic Lesions in ApoE3*Leiden Mice." Cells 9, no. 2 (February 1, 2020): 336. http://dx.doi.org/10.3390/cells9020336.

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Unstable atherosclerotic plaques frequently show plaque angiogenesis which increases the chance of rupture and thrombus formation leading to infarctions. Hypoxia plays a role in angiogenesis and inflammation, two processes involved in the pathogenesis of atherosclerosis. We aim to study the effect of resolution of hypoxia using carbogen gas (95% O2, 5% CO2) on the remodeling of vein graft accelerated atherosclerotic lesions in ApoE3*Leiden mice which harbor plaque angiogenesis. Single treatment resulted in a drastic decrease of intraplaque hypoxia, without affecting plaque composition. Daily treatment for three weeks resulted in 34.5% increase in vein graft patency and increased lumen size. However, after three weeks intraplaque hypoxia was comparable to the controls, as were the number of neovessels and the degree of intraplaque hemorrhage. To our surprise we found that three weeks of treatment triggered ROS accumulation and subsequent Hif1a induction, paralleled with a reduction in the macrophage content, pointing to an increase in lesion stability. Similar to what we observed in vivo, in vitro induction of ROS in bone marrow derived macrophages lead to increased Hif1a expression and extensive DNA damage and apoptosis. Our study demonstrates that carbogen treatment did improve vein graft patency and plaque stability and reduced intraplaque macrophage accumulation via ROS mediated DNA damage and apoptosis but failed to have long term effects on hypoxia and intraplaque angiogenesis.
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2

Wu, Wen, Xiaobo Li, Guangfeng Zuo, Jiangqin Pu, Xinlei Wu, and Shaoliang Chen. "The Role of Angiogenesis in Coronary Artery Disease: A Double-Edged Sword: Intraplaque Angiogenesis in Physiopathology and Therapeutic Angiogenesis for Treatment." Current Pharmaceutical Design 24, no. 4 (April 24, 2018): 451–64. http://dx.doi.org/10.2174/1381612824666171227220815.

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Angiogenesis is described as a sprouting and growth process of new blood vessels from pre-existing vasculature. The relationship between angiogenesis and coronary artery disease (CAD) is double-sided. On one hand, angiogenesis within plaques is responsible for facilitating the growth and vulnerability of plaques by causing intraplaque hemorrhage and inflammatory cell influx, and overabundance of erythrocytes and inflammatory cells within a plaque probably causes plaque rupture, further leading to acute coronary syndrome. Therefore, inhibiting intraplaque angiogenesis has been considered as a potential therapeutic target for CAD. On the other hand, aiming at improving reperfusion to the ischemic myocardium in patients with CAD, angiogenesis promoting has been utilized as a therapeutic approach to expand myocardial microvascular network. Current strategies include direct administration of angiogenic growth factors (protein therapy), promoting angiogenic genes expression in vivo (gene therapy), and delivering stem cells (cell therapy) or exosomes (cell free therapy). This article will start by clarifying the basic concept of angiogenesis, interpret the mechanism of excessive intraplaque angiogenesis in atherosclerosis, and discuss its role in the growth and vulnerability of plaques. Then we will focus on the four distinct strategies of therapeutic angiogenesis. Despite promising animal studies and smallscale clinical trials of therapeutic angiogenesis in patients with ischemic heart disease, investigations have far not shown definite evidence of clinical efficacy. Hence, while acknowledging future work that remains to be done to validate the clinical results, we reviewed the critical challenges in this arena and highlighted the exciting progress that has occurred recently.
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3

Parma, Laura, Fabiana Baganha, Paul H. A. Quax, and Margreet R. de Vries. "Plaque angiogenesis and intraplaque hemorrhage in atherosclerosis." European Journal of Pharmacology 816 (December 2017): 107–15. http://dx.doi.org/10.1016/j.ejphar.2017.04.028.

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4

Baganha, Fabiana, Thijs J. Sluiter, Rob C. M. de Jong, Louise A. van Alst, Hendrika A. B. Peters, J. Wouter Jukema, Mirela Delibegovic, Knut Pettersson, Paul H. A. Quax, and Margreet R. de Vries. "Phosphorylcholine Monoclonal Antibody Therapy Decreases Intraplaque Angiogenesis and Intraplaque Hemorrhage in Murine Vein Grafts." International Journal of Molecular Sciences 23, no. 21 (November 7, 2022): 13662. http://dx.doi.org/10.3390/ijms232113662.

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Phosphorylcholine (PC) is one of the main oxLDL epitopes playing a central role in atherosclerosis, due to its atherogenic and proinflammatory effects. PC can be cleared by natural IgM antibodies and low levels of these antibodies have been associated with human vein graft (VG) failure. Although PC antibodies are recognized for their anti-inflammatory properties, their effect on intraplaque angiogenesis (IPA) and intraplaque hemorrhage (IPH)—interdependent processes contributing to plaque rupture—are unknown. We hypothesized that new IgG phosphorylcholine antibodies (PC-mAb) could decrease vulnerable lesions in murine VGs.Therefore, hypercholesterolemic male ApoE3*Leiden mice received a (donor) caval vein interposition in the carotid artery and weekly IP injections of (5 mg/kg) PCmAb (n = 11) or vehicle (n = 12) until sacrifice at day 28. We found that PCmAb significantly decreased vein graft media (13%), intima lesion (25%), and increased lumen with 32% compared to controls. PCmAb increased collagen content (18%) and decreased macrophages presence (31%). PCmAb resulted in 23% decreased CD163+ macrophages content in vein grafts whereas CD163 expression was decreased in Hb:Hp macrophages. PCmAb significantly lowered neovessel density (34%), EC proliferation and migration with/out oxLDL stimulation. Moreover, PCmAb enhanced intraplaque angiogenic vessels maturation by increasing neovessel pericyte coverage in vivo (31%). Together, this resulted in a 62% decrease in IPH. PCmAb effectively inhibits murine atherosclerotic lesion formation in vein grafts by reducing IPA and IPH via decreased neovessel density and macrophages influx and increased neovessel maturation. PC-mAb therefore holds promise as a new therapeutic approach to prevent vein graft disease.
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Ogata, Atsushi, Masatou Kawashima, Tomihiro Wakamiya, Masashi Nishihara, Jun Masuoka, Yukiko Nakahara, Ryo Ebashi, et al. "Carotid artery stenosis with a high-intensity signal plaque on time-of-flight magnetic resonance angiography and association with evidence of intraplaque hypoxia." Journal of Neurosurgery 126, no. 6 (July 2016): 1873–78. http://dx.doi.org/10.3171/2016.4.jns16349.

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OBJECTIVEHypoxia induces angiogenesis and plays a major role in the progression of carotid plaques. During carotid intervention, plaques with high-intensity signals on time-of-flight (TOF) magnetic resonance angiography (MRA) often cause ischemic stroke and embolic complications. However, the role of intraplaque hypoxia before carotid endarterectomy (CEA) and carotid artery stenting is not presently understood. In this study the authors aimed to investigate the relationship between intraplaque hypoxia and MRA findings.METHODSNineteen consecutive patients with 20 carotid artery stenoses who underwent CEA at Saga University Hospital between August 2008 and December 2014 were enrolled in the study. The expressions of hypoxia-inducible transcription factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were analyzed by immunohistochemical analysis. In addition, the relationship between the findings on TOF MRA and pathology for the carotid plaques was analyzed.RESULTSHigh-intensity plaques on TOF MRA showed higher expression levels of HIF-1α (p = 0.015) and VEGF (p = 0.007) compared with isointensity plaques. The rate of intraplaque hemorrhage (IPH) on TOF MRA was also significantly higher in the high-intensity plaques than in the isointensity plaques (p = 0.024). Finally, the mean number of neovessels was significantly higher in those without plaque hemorrhage than in those with plaque hemorrhage (p = 0.010).CONCLUSIONSPlaques with high-intensity signals on TOF MRA were associated with IPH and evidence of intraplaque hypoxia. This fact may represent an opportunity to establish novel therapeutic agents targeting intraplaque hypoxia.
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6

Baganha, Fabiana, Rob C. M. de Jong, Erna A. Peters, Wietske Voorham, J. Wouter Jukema, Mirela Delibegovic, Margreet R. de Vries, and Paul H. A. Quax. "Atorvastatin pleiotropically decreases intraplaque angiogenesis and intraplaque haemorrhage by inhibiting ANGPT2 release and VE-Cadherin internalization." Angiogenesis 24, no. 3 (February 7, 2021): 567–81. http://dx.doi.org/10.1007/s10456-021-09767-9.

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Abstract Objective Statins pleiotropically provide additional benefits in reducing atherosclerosis, but their effects on intraplaque angiogenesis (IPA) and hemorrhage (IPH) remain unclear. Therefore, we discriminated statin’s lipid-lowering dependent and independent effects on IPA and IPH. Approach and results ApoE3*Leiden mice are statin-responsive due to ApoE and LDLR presence, but also allow to titrate plasma cholesterol levels by diet. Therefore, ApoE3*Leiden mice were fed a high-cholesterol-inducing-diet (HCD) with or without atorvastatin (A) or a moderate-cholesterol-inducing-diet (MCD). Mice underwent vein graft surgery to induce lesions with IPA and IPH. Cholesterol levels were significantly reduced in MCD (56%) and HCD + A (39%) compared to HCD with no significant differences between MCD and HCD + A. Both MCD and HCD + A have a similar reduction in vessel remodeling and inflammation comparing to HCD. IPA was significantly decreased by 30% in HCD + A compared to HCD or MCD. Atorvastatin treatment reduced the presence of immature vessels by 34% vs. HCD and by 25% vs. MCD, resulting in a significant reduction of IPH. Atorvastatin’s anti-angiogenic capacity was further illustrated by a dose-dependent reduction of ECs proliferation and migration. Cultured mouse aortic-segments lost sprouting capacity upon atorvastatin treatment and became 30% richer in VE-Cadherin expression and pericyte coverage. Moreover, Atorvastatin inhibited ANGPT2 release and decreased VE-Cadherin(Y685)-phosphorylation in ECs. Conclusions Atorvastatin has beneficial effects on vessel remodeling due to its lipid-lowering capacity. Atorvastatin has strong pleiotropic effects on IPA by decreasing the number of neovessels and on IPH by increasing vessel maturation. Atorvastatin improves vessel maturation by inhibiting ANGPT2 release and phospho(Y658)-mediated VE-Cadherin internalization.
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7

Sun, Yan, Xiao-li Liu, Dai Zhang, Fang Liu, Yu-jing Cheng, Yue Ma, Yu-jie Zhou, and Ying-xin Zhao. "Platelet-Derived Exosomes Affect the Proliferation and Migration of Human Umbilical Vein Endothelial Cells Via miR-126." Current Vascular Pharmacology 17, no. 4 (June 11, 2019): 379–87. http://dx.doi.org/10.2174/1570161116666180313142139.

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Background:Intraplaque angiogenesis, the process of generating new blood vessels mediated by endothelial cells, contributes to plaque growth, intraplaque hemorrhage, and thromboembolic events. Platelet-derived Exosomes (PLT-EXOs) affect angiogenesis in multiple ways. The ability of miR-126, one of the best-characterized miRNAs that regulates angiogenesis, carried by PLT-EXOs to influence angiogenesis via the regulation of the proliferation and migration of endothelial cells is unknown. In this study, we aimed to investigate the effects of PLT-EXOs on angiogenesis by Human Umbilical Vein Endothelial Cells (HUVECs).Methods:We evaluated the levels of miR-126 and angiogenic factors in PLT-EXOs from Acute Coronary Syndrome (ACS) patients and healthy donors by real-time Polymerase Chain Reaction (PCR) and western blotting. We incubated HUVECs with PLT-EXOs and measured cell proliferation and migration with the Cell Counting Kit-8 assay and scratch assay, respectively. We also investigated the expression of miR-126 and angiogenic factors in HUVECs after exposure to PLT-EXOs by western blotting and real-time PCR.Results:PLT-EXOs from ACS patients contained higher levels of miR-126 and angiogenic factors, including Vascular Endothelial Growth Factor (VEGF), basic Fibroblast Growth Factor (bFGF), and Transforming Growth Factor Beta 1 (TGF-β1), than those from healthy donors (p<0.05). Moreover, the levels of exosomal miR-126 and angiogenic factors were increased after stimulation with thrombin (p<0.01). HUVEC proliferation and migration were promoted by treatment with activated PLT-EXOs (p<0.01); they were accompanied by the over-expression of miR-126 and angiogenic factors, including VEGF, bFGF, and TGF-β1 (p<0.01).Conclusion:Activated PLT-EXOs promoted the proliferation and migration of HUVECs, and the overexpression of miR-126 and angiogenic factors, thereby elucidating potential new therapeutic targets for intraplaque angiogenesis.
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8

Li, Bo, Yue Zhang, Runting Yin, Wei Zhong, Rui Chen, and Jinchuan Yan. "Activating CD137 Signaling Promotes Sprouting Angiogenesis via Increased VEGFA Secretion and the VEGFR2/Akt/eNOS Pathway." Mediators of Inflammation 2020 (October 24, 2020): 1–19. http://dx.doi.org/10.1155/2020/1649453.

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Combination of antiangiogenesis and immunotherapy may be an effective strategy for treatment of solid tumors. Our previous work reported that activation of CD137 signaling promotes intraplaque angiogenesis. A number of studies have demonstrated that vascular endothelial growth factor receptor 2 (VEGFR2) is a key target for angiogenesis. However, it is unknown whether CD137-mediated angiogenesis is related to VEGFR2. In this study, we investigated the effect of CD137 on the VEGFR2 expression and explored the underlying mechanisms of CD137-mediated angiogenesis. Knock-out of CD137 in ApoE-/- mice significantly decreased neovessel density in atherosclerotic plaques. CD137 silencing or inhibition attenuated endothelial cell (ECs) proliferation, migration, and tube formation. We found activation of CD137 signaling for increased VEGFR2 transcription and translation steadily. Moreover, CD137 signaling activated phosphorylated VEGFR2 (Tyr1175) and the downstream Akt/eNOS pathway, whereas neutralizing CD137 signaling weakened the activation of VEGFR2 and the downstream Akt/eNOS pathway. The aortic ring assay further demonstrated that CD137 signaling promoted ECc sprouting. Inhibition of VEGFR2 by siRNA or XL184 (cabozantinib) and inhibition of downstream signaling by LY294002 (inhibits AKT activation) and L-NAME (eNOS inhibitor) remarkably abolished proangiogenic effects of CD137 signaling both in vitro and ex vivo. In addition, the condition medium from CD137-activated ECs and vascular endothelial growth factor A (VEGFA) had similar effects on ECs that expressed high VEGFR2. Additionally, activating CD137 signaling promoted endothelial secretion of VEGFA, while blocking CD137 signaling attenuated VEGFA secretion. In conclusion, activation of CD137 signaling promoted sprouting angiogenesis by increased VEGFA secretion and the VEGFR2/Akt/eNOS pathway. These findings provide a basis for stabilizing intraplaque angiogenesis through VEGFR2 intervatioin, as well as cancer treatment via combination of CD137 agonists and specific VEGFR2 inhibitors.
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9

Higashida, Tetsuhiro, Hiroshi Kanno, Masato Nakano, Kengo Funakoshi, and Isao Yamamoto. "Expression of hypoxia-inducible angiogenic proteins (hypoxia-inducible factor–1α, vascular endothelial growth factor, and E26 transformation-specific–1) and plaque hemorrhage in human carotid atherosclerosis." Journal of Neurosurgery 109, no. 1 (July 2008): 83–91. http://dx.doi.org/10.3171/jns/2008/109/7/0083.

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Object Plaque hemorrhage in carotid atherosclerosis promotes plaque progression, resulting in cerebrovascular disease. Hypoxia inducible factor–1α (HIF-1α) induces angiogenesis via the expression of vascular endothelial growth factor (VEGF) and E26 transformation-specific–1 (Ets-1). The authors investigated human carotid plaques to determine whether these hypoxia-inducible angiogenic proteins play a major role in intraplaque angiogenesis and hemorrhage. Methods The expression of HIF-1α, VEGF, and Ets-1 was analyzed using immunohistochemistry and Western blotting in 29 human carotid plaques obtained at carotid endarterectomy. The authors investigated the relationship between plaque characteristics and clinical symptoms. Results A higher incidence of plaque hemorrhage was observed in plaques associated with symptoms than in those without symptoms (p = 0.03). Hypoxia-inducible factor–1α, VEGF, and Ets-1 coexisted in the deep layer of plaque, where angiogenesis was remarkably developed; the expression levels of HIF-1α, VEGF, and Ets-1 were significantly enhanced in the main lesion of the plaque (p < 0.01). Symptomatic plaques showed higher expression of VEGF (p = 0.04) than asymptomatic plaques. Plaques with hemorrhage showed a higher incidence of plaque ulcer (p = 0.001) and higher expression of Ets-1 (p = 0.03) than those without hemorrhage. Moreover, significantly increased expressions of VEGF (p = 0.01) and Ets-1 (p = 0.006) were observed in plaques with not only hemorrhages but also ulcers and severe stenosis. Conclusions The findings in this study suggest that hypoxia-inducible angiogenic proteins in human carotid atherosclerosis promote intraplaque angiogenesis, which can induce plaque hemorrhage and progression.
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10

Van der Veken, Bieke, Guido R. Y. De Meyer, and Wim Martinet. "Axitinib attenuates intraplaque angiogenesis, haemorrhages and plaque destabilization in mice." Vascular Pharmacology 100 (January 2018): 34–40. http://dx.doi.org/10.1016/j.vph.2017.10.004.

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11

Sun, Chang, Na Xi, Zhijun Sun, Xinxin Zhang, Xiaowei Wang, Huiyang Cao, and Xiaowei Jia. "The Relationship between Intracarotid Plaque Neovascularization and Lp (a) and Lp-PLA2 in Elderly Patients with Carotid Plaque Stenosis." Disease Markers 2022 (April 21, 2022): 1–6. http://dx.doi.org/10.1155/2022/6154675.

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The aim of this study was to investigate the relationship between carotid plaque neovascularization and lipoprotein (a) [Lp (a)], lipoprotein-associated phospholipase A2 (Lp-PLA2) in elderly patients with carotid plaque stenosis. One hundred elderly patients with carotid plaque stenosis diagnosed in our hospital from January 2020 to January 2022 were retrospectively analyzed and divided into stable ( n = 62 ) and unstable ( n = 38 ) groups according to whether the plaque was stable or not. Plasma Lp (a), Lp-PLA2, apoA, and apoB levels were measured; intraplaque angiogenesis (IPN) scores were examined by contrast-enhanced ultrasound (CEUS) to assess IPN grade in patients; and Pearson correlation was used to analyze the relationship between plasma Lp (a) and Lp-PLA2 levels and plaque characteristics and angiogenesis. The maximum thickness and total thickness of carotid plaque in the unstable group were significantly greater than those in the stable group ( P < 0.05 ); the IPN grade was mainly grade III and IV in the unstable group and grade II in the stable group, and the IPN score was significantly higher in the unstable group than in the stable group ( P < 0.05 ); there was no significant difference in the plasma apoA and apoB levels between the two groups ( P > 0.05 ), and the plasma Lp (a) and Lp-PLA2 levels were significantly higher in the unstable group than in the stable group ( P < 0.05 ); the neovascular grade, plasma Lp-PLA2, and Lp (a) levels were significantly increased ( P < 0.05 ); the plasma Lp (a) and Lp-PLA2 levels were positively correlated with the maximum plaque thickness, total plaque thickness, degree of stenosis, and angiogenesis ( P < 0.05 ). The plasma levels of Lp (a) and Lp-PLA2 are positively correlated with intraplaque angiogenesis, and their levels can reflect the stability of carotid plaques.
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Finn, Aloke V., Hirokuni Akahori, Liang Guo, Rohini Polavarapu, Vinit Karmali, Adrienne King, Cheol Choi, et al. "ALTERNATIVE MACROPHAGES PROMOTE INTRAPLAQUE ANGIOGENESIS AND VASCULAR PERMEABILITY IN HUMAN ATHEROSCLEROSIS." Journal of the American College of Cardiology 67, no. 13 (April 2016): 2241. http://dx.doi.org/10.1016/s0735-1097(16)32242-2.

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13

Koutouzis, Michael, Alexandros Nomikos, Savvas Nikolidakis, Vasiliki Tzavara, Vasilios Andrikopoulos, Nikolaos Nikolaou, Calypso Barbatis, and Zenon S. Kyriakides. "Statin treated patients have reduced intraplaque angiogenesis in carotid endarterectomy specimens." Atherosclerosis 192, no. 2 (June 2007): 457–63. http://dx.doi.org/10.1016/j.atherosclerosis.2007.01.035.

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14

Finn, Aloke V., Frank D. Kolodgie, Masataka Nakano, and Renu Virmani. "The Differences Between Neovascularization of Chronic Total Occlusion and Intraplaque Angiogenesis." JACC: Cardiovascular Imaging 3, no. 8 (August 2010): 806–10. http://dx.doi.org/10.1016/j.jcmg.2010.03.011.

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15

Perrotta, Paola, Bieke Van der Veken, Pieter Van Der Veken, Isabel Pintelon, Laurence Roosens, Elias Adriaenssens, Vincent Timmerman, Pieter-Jan Guns, Guido R. Y. De Meyer, and Wim Martinet. "Partial Inhibition of Glycolysis Reduces Atherogenesis Independent of Intraplaque Neovascularization in Mice." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 5 (May 2020): 1168–81. http://dx.doi.org/10.1161/atvbaha.119.313692.

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Objective: Intraplaque neovascularization is an important feature of unstable human atherosclerotic plaques. However, its impact on plaque formation and stability is poorly studied. Because proliferating endothelial cells generate up to 85% of their ATP from glycolysis, we investigated whether pharmacological inhibition of glycolytic flux by the small-molecule 3PO (3-[3-pyridinyl]-1-[4-pyridinyl]-2-propen-1-one) could have beneficial effects on plaque formation and composition. Approach and Results: ApoE −/ − (apolipoprotein E deficient) mice treated with 3PO (50 µg/g, ip; 4×/wk, 4 weeks) showed a metabolic switch toward ketone body formation. Treatment of ApoE −/− Fbn1 C1039G+/− mice with 3PO (50 µg/g, ip) either after 4 (preventive, twice/wk, 10 weeks) or 16 weeks of Western diet (curative, 4×/wk, 4 weeks) inhibited intraplaque neovascularization by 50% and 38%, respectively. Plaque formation was significantly reduced in all 3PO-treated animals. This effect was independent of intraplaque neovascularization. In vitro experiments showed that 3PO favors an anti-inflammatory M2 macrophage subtype and suppresses an M1 proinflammatory phenotype. Moreover, 3PO induced autophagy, which in turn impaired NF-κB (nuclear factor-kappa B) signaling and inhibited TNF-α (tumor necrosis factor-alpha)–mediated VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) upregulation. Consistently, a preventive 3PO regimen reduced endothelial VCAM-1 expression in vivo. Furthermore, 3PO improved cardiac function in ApoE −/− Fbn1 C1039G+/− mice after 10 weeks of treatment. Conclusions: Partial inhibition of glycolysis restrained intraplaque angiogenesis without affecting plaque composition. However, less plaques were formed, which was accompanied by downregulation of endothelial adhesion molecules—an event that depends on autophagy induction. Inhibition of coronary plaque formation by 3PO resulted in an overall improved cardiac function.
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Dabravolski, Siarhei A., Alexander M. Markin, Elena R. Andreeva, Ilya I. Eremin, Alexander N. Orekhov, and Alexandra A. Melnichenko. "Molecular Mechanisms Underlying Pathological and Therapeutic Roles of Pericytes in Atherosclerosis." International Journal of Molecular Sciences 23, no. 19 (October 1, 2022): 11663. http://dx.doi.org/10.3390/ijms231911663.

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Pericytes are multipotent mesenchymal stromal cells playing an active role in angiogenesis, vessel stabilisation, maturation, remodelling, blood flow regulation and are able to trans-differentiate into other cells of the mesenchymal lineage. In this review, we summarised recent data demonstrating that pericytes play a key role in the pathogenesis and development of atherosclerosis (AS). Pericytes are involved in lipid accumulation, inflammation, growth, and vascularization of the atherosclerotic plaque. Decreased pericyte coverage, endothelial and pericyte dysfunction is associated with intraplaque angiogenesis and haemorrhage, calcification and cholesterol clefts deposition. At the same time, pericytes can be used as a novel therapeutic target to promote vessel maturity and stability, thus reducing plaque vulnerability. Finally, we discuss recent studies exploring effective AS treatments with pericyte-mediated anti-atherosclerotic, anti-inflammatory and anti-apoptotic effects.
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Van Der Veken, Bieke, Guido De Meyer, and Wim Martinet. "Inhibition of glycolysis reduces intraplaque angiogenesis in a mouse model of advanced atherosclerosis." Atherosclerosis 263 (August 2017): e23. http://dx.doi.org/10.1016/j.atherosclerosis.2017.06.098.

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Guo, Muyi, Yan Cai, Chunliu He, and Zhiyong Li. "Coupled Modeling of Lipid Deposition, Inflammatory Response and Intraplaque Angiogenesis in Atherosclerotic Plaque." Annals of Biomedical Engineering 47, no. 2 (November 28, 2018): 439–52. http://dx.doi.org/10.1007/s10439-018-02173-1.

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19

Baganha, F., M. De Vries, P. Knutt, and PHA Quax. "P355A monoclonal human IgG1 phosphorylcholine antibody reduces vein graft remodelling, angiogenesis and intraplaque haemorrhage." Cardiovascular Research 114, suppl_1 (April 1, 2018): S91. http://dx.doi.org/10.1093/cvr/cvy060.267.

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Liu, Xiao Qiong, Yang Mao, Bo Wang, Xiao Ting Lu, Wen Wu Bai, Yuan Yuan Sun, Yan Liu, et al. "Specific Matrix Metalloproteinases Play Different Roles in Intraplaque Angiogenesis and Plaque Instability in Rabbits." PLoS ONE 9, no. 9 (September 18, 2014): e107851. http://dx.doi.org/10.1371/journal.pone.0107851.

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Dzobo, K. E. "Carotid endarterectomy plaques of patients with elevated levels of lipoprotein(a) demonstrate increased intraplaque angiogenesis." Atherosclerosis 355 (August 2022): 3. http://dx.doi.org/10.1016/j.atherosclerosis.2022.06.097.

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22

Perrotta, Paola, Isabel Pintelon, Margreet R. de Vries, Paul H. A. Quax, Jean-Pierre Timmermans, Guido R. Y. De Meyer, and Wim Martinet. "Three-Dimensional Imaging of Intraplaque Neovascularization in a Mouse Model of Advanced Atherosclerosis." Journal of Vascular Research 57, no. 6 (2020): 348–54. http://dx.doi.org/10.1159/000508449.

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Multiple lines of evidence suggest that intraplaque (IP) neovascularization promotes atherosclerotic plaque growth, destabilization, and rupture. However, pharmacological inhibition of IP neovascularization remains largely unexplored due to the limited number of animal models that develop IP neovessels and the lack of reliable methods for visualizing IP angiogenesis. Here, we applied 3D confocal microscopy with an optimized tissue-clearing process, immunolabeling-enabled three-dimensional imaging of solvent-cleared organs, to visualize IP neovessels in apolipoprotein E-deficient (ApoE<sup>−/−</sup>) mice carrying a heterozygous mutation (C1039+/−) in the fibrillin-1 gene. Unlike regular ApoE<sup>−/−</sup> mice, this mouse model is characterized by the presence of advanced plaques with evident IP neovascularization. Plaques were stained with antibodies against endothelial marker CD31 for 3 days, followed by incubation with fluorescently labeled secondary antibodies. Subsequent tissue clearing with dichloromethane (DCM)/methanol, DCM, and dibenzyl ether allowed easy visualization and 3D reconstruction of the IP vascular network while plaque morphology remained intact.
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23

Sluiter, Thijs J., Jaap D. van Buul, Stephan Huveneers, Paul H. A. Quax, and Margreet R. de Vries. "Endothelial Barrier Function and Leukocyte Transmigration in Atherosclerosis." Biomedicines 9, no. 4 (March 24, 2021): 328. http://dx.doi.org/10.3390/biomedicines9040328.

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The vascular endothelium is a highly specialized barrier that controls passage of fluids and migration of cells from the lumen into the vessel wall. Endothelial cells assist leukocytes to extravasate and despite the variety in the specific mechanisms utilized by different leukocytes to cross different vascular beds, there is a general principle of capture, rolling, slow rolling, arrest, crawling, and ultimately diapedesis via a paracellular or transcellular route. In atherosclerosis, the barrier function of the endothelium is impaired leading to uncontrolled leukocyte extravasation and vascular leakage. This is also observed in the neovessels that grow into the atherosclerotic plaque leading to intraplaque hemorrhage and plaque destabilization. This review focuses on the vascular endothelial barrier function and the interaction between endothelial cells and leukocytes during transmigration. We will discuss the role of endothelial dysfunction, transendothelial migration of leukocytes and plaque angiogenesis in atherosclerosis.
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24

Sluimer, Judith C., Jean-Marie Gasc, Job L. van Wanroij, Natasja Kisters, Mathijs Groeneweg, Maarten D. Sollewijn Gelpke, Jack P. Cleutjens, et al. "Hypoxia, Hypoxia-Inducible Transcription Factor, and Macrophages in Human Atherosclerotic Plaques Are Correlated With Intraplaque Angiogenesis." Journal of the American College of Cardiology 51, no. 13 (April 2008): 1258–65. http://dx.doi.org/10.1016/j.jacc.2007.12.025.

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Qiu, Juhui, Daoxi Lei, Jianjun Hu, Tieying Yin, Kang Zhang, Donghong Yu, and Guixue Wang. "Effect of intraplaque angiogenesis to atherosclerotic rupture-prone plaque induced by high shear stress in rabbit model." Regenerative Biomaterials 4, no. 4 (July 7, 2017): 215–22. http://dx.doi.org/10.1093/rb/rbx007.

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Dentelli, Patrizia, Arturo Rosso, Antonina Balsamo, Sofia Colmenares Benedetto, Annarita Zeoli, Marco Pegoraro, Giovanni Camussi, Luigi Pegoraro, and Maria Felice Brizzi. "C-KIT, by interacting with the membrane-bound ligand, recruits endothelial progenitor cells to inflamed endothelium." Blood 109, no. 10 (February 8, 2007): 4264–71. http://dx.doi.org/10.1182/blood-2006-06-029603.

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Abstract We investigated the role of c-Kit and the membrane-bound ligand (mbKitL) in endothelial progenitor cell (EPC) recruitment by microvascular endothelial cells (ECs). We demonstrated that inflammatory activation induced the expression of the mbKitL on ECs both in vitro and in vivo, and that recruitment of EPCs depended on c-Kit/mbKitL interaction. Depletion of endogenous c-Kit or inhibition of c-Kit enzymatic activity by imatinib mesylate prevented adhesion of EPCs to activated ECs both in vitro and in vivo, indicating that a functional c-Kit on EPCs is essential. We also demonstrate that Akt was the downstream molecule regulating cell adhesion. A potential role of the c-Kit/mbKitL interaction in pathological settings is sustained by the expression of the mbKitL on ECs lining intraplaque neovessels. Thus, our results provide new insights into the mechanisms underlying EPC recruitment and the bases for novel strategies to hinder pathological angiogenesis.
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Van Der Veken, Bieke, Guido De Meyer, and Wim Martinet. "Inhibition of VEGF receptor signaling attenuates intraplaque angiogenesis and plaque destabilization in a mouse model of advanced atherosclerosis." Atherosclerosis 263 (August 2017): e33-e34. http://dx.doi.org/10.1016/j.atherosclerosis.2017.06.129.

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Camaré, Caroline, Corinne Vanucci-Bacqué, Nathalie Augé, Mélanie Pucelle, Corinne Bernis, Audrey Swiader, Michel Baltas, Florence Bedos-Belval, Robert Salvayre, and Anne Nègre-Salvayre. "4-Hydroxynonenal Contributes to Angiogenesis through a Redox-Dependent Sphingolipid Pathway: Prevention by Hydralazine Derivatives." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/9172741.

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The neovascularization of atherosclerotic lesions is involved in plaque development and may contribute to intraplaque hemorrhage and plaque fragilization and rupture. Among the various proangiogenic agents involved in the neovascularization process, proatherogenic oxidized LDLs (oxLDLs) contribute to the formation of tubesviathe generation of sphingosine 1-phosphate (S1P), a major mitogenic and proangiogenic sphingolipid mediator. In this study, we investigated whether 4-hydroxynonenal (4-HNE), an aldehydic lipid oxidation product abundantly present in oxLDLs, contributes to their proangiogenic properties. Immunofluorescence analysis of human atherosclerotic lesions from carotid endarterectomy showed the colocalization of HNE-adducts with CD31, a marker of endothelial cells, suggesting a close relationship between 4-HNE and neovessel formation. In vitro, low 4-HNE concentration (0.5–1 µM) elicited the formation of tubes by human microvascular endothelial cells (HMEC-1), whereas higher concentrations were not angiogenic. The formation of tubes by 4-HNE involved the generation of reactive oxygen species and the activation of the sphingolipid pathway, namely, the neutral type 2 sphingomyelinase and sphingosine kinase-1 (nSMase2/SK-1) pathway, indicating a role for S1P in the angiogenic signaling of 4-HNE. Carbonyl scavengers hydralazine and bisvanillyl-hydralazone inhibited the nSMase2/SK1 pathway activation and the formation of tubes on Matrigel® evoked by 4-HNE. Altogether, these results emphasize the role of 4-HNE in the angiogenic effect of oxLDLs and point out the potential interest of pharmacological carbonyl scavengers to prevent the neovascularization process.
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Giannoni, Maria, and Edoardo Vicenzini. "Focus on the “Unstable” Carotid Plaque: Detection of Intraplaque Angiogenesis with Contrast Ultrasound. Present State and Future Perspectives." Current Vascular Pharmacology 7, no. 2 (April 1, 2009): 180–84. http://dx.doi.org/10.2174/157016109787455626.

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Kostyunin, Alexander, Rinat Mukhamadiyarov, Tatiana Glushkova, Leo Bogdanov, Daria Shishkova, Nikolay Osyaev, Evgeniy Ovcharenko, and Anton Kutikhin. "Ultrastructural Pathology of Atherosclerosis, Calcific Aortic Valve Disease, and Bioprosthetic Heart Valve Degeneration: Commonalities and Differences." International Journal of Molecular Sciences 21, no. 20 (October 9, 2020): 7434. http://dx.doi.org/10.3390/ijms21207434.

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Atherosclerosis, calcific aortic valve disease (CAVD), and bioprosthetic heart valve degeneration (alternatively termed structural valve deterioration, SVD) represent three diseases affecting distinct components of the circulatory system and their substitutes, yet sharing multiple risk factors and commonly leading to the extraskeletal calcification. Whereas the histopathology of the mentioned disorders is well-described, their ultrastructural pathology is largely obscure due to the lack of appropriate investigation techniques. Employing an original method for sample preparation and the electron microscopy visualisation of calcified cardiovascular tissues, here we revisited the ultrastructural features of lipid retention, macrophage infiltration, intraplaque/intraleaflet haemorrhage, and calcification which are common or unique for the indicated types of cardiovascular disease. Atherosclerotic plaques were notable for the massive accumulation of lipids in the extracellular matrix (ECM), abundant macrophage content, and pronounced neovascularisation associated with blood leakage and calcium deposition. In contrast, CAVD and SVD generally did not require vasculo- or angiogenesis to occur, instead relying on fatigue-induced ECM degradation and the concurrent migration of immune cells. Unlike native tissues, bioprosthetic heart valves contained numerous specialised macrophages and were not capable of the regeneration that underscores ECM integrity as a pivotal factor for SVD prevention. While atherosclerosis, CAVD, and SVD show similar pathogenesis patterns, these disorders demonstrate considerable ultrastructural differences.
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Tang, Y. L., Y. Z. Yang, S. Wang, B. H. Dong, W. Q. Sun, H. Y. Jin, Z. X. Xu, X. Ye, and Y. H. Sun. "Tu-P7:25 Compound 48/80 promotes atherosclerotic plaque and intraplaque angiogenesis in apolipoprotein E deficient mice with carotid collar placement." Atherosclerosis Supplements 7, no. 3 (January 2006): 190. http://dx.doi.org/10.1016/s1567-5688(06)80734-8.

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Mao, Yang, Xiaoqiong Liu, Yu Song, Chungang Zhai, and Lei Zhang. "VEGF-A/VEGFR-2 and FGF-2/FGFR-1 but not PDGF-BB/PDGFR-β play important roles in promoting immature and inflammatory intraplaque angiogenesis." PLOS ONE 13, no. 8 (August 20, 2018): e0201395. http://dx.doi.org/10.1371/journal.pone.0201395.

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Parma, Laura, Hendrika A. B. Peters, Thijs J. Sluiter, Karin H. Simons, Paolo Lazzari, Margreet R. de Vries, and Paul H. A. Quax. "bFGF blockade reduces intraplaque angiogenesis and macrophage infiltration in atherosclerotic vein graft lesions in ApoE3*Leiden mice." Scientific Reports 10, no. 1 (September 29, 2020). http://dx.doi.org/10.1038/s41598-020-72992-7.

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Abstract Intraplaque angiogenesis increases the chance of unstable atherosclerotic plaque rupture and thrombus formation leading to myocardial infarction. Basic Fibroblast Growth Factor (bFGF) plays a key role in angiogenesis and inflammation and is involved in the pathogenesis of atherosclerosis. Therefore, we aim to test K5, a small molecule bFGF-inhibitor, on remodelling of accelerated atherosclerotic vein grafts lesions in ApoE3*Leiden mice. K5-mediated bFGF-signalling blockade strongly decreased intraplaque angiogenesis and intraplaque hemorrhage. Moreover, it reduced macrophage infiltration in the lesions by modulating CCL2 and VCAM1 expression. Therefore, K5 increases plaque stability. To study the isolated effect of K5 on angiogenesis and SMCs-mediated intimal hyperplasia formation, we used an in vivo Matrigel-plug mouse model that reveals the effects on in vivo angiogenesis and femoral artery cuff model to exclusively looks at SMCs. K5 drastically reduced in vivo angiogenesis in the matrigel plug model while no effect on SMCs migration nor proliferation could be seen in the femoral artery cuff model. Moreover, in vitro K5 impaired endothelial cells functions, decreasing migration, proliferation and tube formation. Our data show that K5-mediated bFGF signalling blockade in hypercholesterolemic ApoE3*Leiden mice reduces intraplaque angiogenesis, haemorrhage and inflammation. Therefore, K5 is a promising candidate to stabilize advanced atherosclerotic plaques.
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Guo, Liang, Hirokuni Akahori, Rohini Polavarapu, Emannuel Harari, Vinit Karmali, Adrienne L. King, Cheol Ung Choi, et al. "Abstract 648: Alternative Macrophages Promote Atherosclerosis Progression by Increasing Intraplaque Angiogenesis and Vascular Permeability via HIF-1 alpha/VEGF-A-dependent Pathway." Arteriosclerosis, Thrombosis, and Vascular Biology 36, suppl_1 (May 2016). http://dx.doi.org/10.1161/atvb.36.suppl_1.648.

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Background: Alternative macrophages exist in human atherosclerosis but their role in atherogenesis remains uncertain. Intraplaque hemorrhage (IPH) is an important stimulus driving alternative macrophage polarization. Intake of hemoglobin (Hb) by the hemoglobin: haptoglobin receptor CD163 leads to a distinct non-foam cell phenotype termed M(Hb). These cells demonstrate upregulation of CD163, lack of lipid retention, and anti-oxidative properties, characteristics considered ‘atheroprotective’. Here we reveal an unexpected but important pathogenic role for M(Hb) in atherosclerosis. Objectives: To determine the role of M(Hb) macrophages in human intraplaque angiogenesis and vascular permeability. Methods: Using human atherosclerotic samples, cultured cells, and a mouse model of IPH, we investigated the role of IPH on macrophage function with respect to angiogenesis and vascular permeability. Results: Within M(Hb) activation of hypoxia-inducible factor-1 alpha (HIF-1) via inhibition of prolyl hydroxylases promotes intraplaque angiogenesis and vascular permeability. In human carotid plaques, alternative CD163 positive macrophages were found to be highly associated with plaque vascularity and expressed high levels of HIF1- and vascular endothelial growth factor-A (VEGF-A). Supernatants from hemoglobin:haptoglobin differentiated M(Hb) macrophages increased endothelial permeability and led to internalization of the endothelial barrier protein vascular endothelial cadherin (VE-cadherin) via activation of VEGF receptor 2 (VEGFR2). Areas of plaque demonstrating high density CD163 high macrophage subsets showed irregular VE-cadherin immunostaining and diffuse perivascular collections of von Willebrand factor suggesting microvessel incompetence. Finally, in brachiocephalic plaques of one-year-old apoE -/- and apoE -/- CD163 -/- mice, CD163 deficiency significantly reduced plaque progression, lesion size, and intraplaque hemorrhage, but had little effect on lesions uncomplicated by hemorrhage. Conclusions: Our findings provide a novel non-lipid driven mechanism by which alterative M(Hb) macrophages promote plaque neoangiogenesis and microvessel incompetence via a HIF-1/VEGF-A-dependent pathway.
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Cai, Yan, Jichao Pan, and Zhiyong Li. "Mathematical modeling of intraplaque neovascularization and hemorrhage in a carotid atherosclerotic plaque." BioMedical Engineering OnLine 20, no. 1 (April 29, 2021). http://dx.doi.org/10.1186/s12938-021-00878-4.

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Abstract Background Growing experimental evidence has identified neovascularization from the adventitial vasa vasorum and induced intraplaque hemorrhage (IPH) as critical indicators during the development of vulnerable atherosclerotic plaques. In this study, we propose a mathematical model incorporating intraplaque angiogenesis and hemodynamic calculation of the microcirculation, to obtain the quantitative evaluation of the influences of intraplaque neovascularization and hemorrhage on vulnerable plaque development. A two-dimensional nine-point model of angiogenic microvasculature is generated based on the histology of a patient’s carotid plaque. The intraplaque angiogenesis model includes three key cells (endothelial cells, smooth muscle cells, and macrophages) and three key chemical factors (vascular endothelial growth factors, extracellular matrix, and matrix metalloproteinase), which densities and concentrations are described by a series of reaction–diffusion equations. The hemodynamic calculation by coupling the intravascular blood flow, the extravascular plasma flow, and the transvascular transport is carried out on the generated angiogenic microvessel network. We then define the IPH area by using the plasma concentration in the interstitial tissue, as well as the extravascular transport across the capillary wall. Results The simulational results reproduce a series of pathophysiological phenomena during the atherosclerotic plaque progression. It is found that the high microvessel density region at the shoulder areas and the extravascular flow across the leaky wall of the neovasculature contribute to the IPH observed widely in vulnerable plaques. The simulational results are validated by both the in vivo MR imaging data and in vitro experimental observations and show significant consistency in quantity ground. Moreover, the sensitivity analysis of model parameters reveals that the IPH area and extent can be reduced significantly by decreasing the MVD and the wall permeability of the neovasculature. Conclusions The current quantitative model could help us to better understand the roles of microvascular and intraplaque hemorrhage during the carotid plaque progression.
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De Vries, M., F. Baganha, R. C. M. De Jong, H. A. B. Peters, K. Petterson, and P. H. A. Quax. "IgG1 phosphorylcholine ameliorates plaque stability via reduced intraplaque angiogenesis and intraplaque haemorrhage in a murine atherosclerosis model." European Heart Journal 41, Supplement_2 (November 1, 2020). http://dx.doi.org/10.1093/ehjci/ehaa946.3650.

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Abstract Background Phosphorylcholine, (PC) the polar headgroup of the dominating membrane phospholipid phosphatidylcholine, is one of the main oxLDL epitopes and an important pro-inflammatory damage associated molecular pattern. Experimental and epidemiologic data show that natural anti-PC IgM protect against cardiovascular disease. Within atherosclerotic lesions, inflammatory and angiogenesis processes are interdependent and contribute to plaque destabilization. Atherosclerotic lesion resident CD163+ macrophages promote leukocyte infiltration but also induce angiogenesis and vessel permeability by secreting VEGFA. PC antibodies are recognized for their anti-inflammatory properties. However, the effect of PC antibodies on intraplaque angiogenesis (IPA) and intraplaque hemorrhage (IPH), the main entrance route for inflammatory cells in advanced lesions, is unknown. Purpose To investigate the therapeutic effect of a new IgG1 PC antibody (PCmAB) on lesion development, IPA and IPH in murine vein graft atherosclerosis. Methods All animal experiments were performed in compliance with Dutch government guidelines and the Directive 2010/63/EU of the European Parliament. Hypercholesterolemic male ApoE3*Leiden mice received a (donor) caval vein interposition in the carotid artery. Mice received weekly ip injections of (5mg/kg) PCmAb (n=11) or vehicle (n=12) until sacrifice at day 28. Immunohistochemistry was used to evaluate vein graft morphometry and lesion composition including IPA and IPH. PCmAB isolated effects on pro-angiogenic and pro-inflammatory behaviour was investigated in vitro in HUVECs and Hemoglobin (Hb):Haptoglobin (Hp)-cultured THP-1 macrophages. Results PCmAB treatment decreased vein graft media area (13%) and intima lesion (25%), but more importantly increased lumen area with 53% when compared to vehicle treatment. PCmAb improved lesion stability by increasing collagen content (18%) and by decreasing macrophages presence (31%). VCAM-1 and ICAM-1 expression in the vessel wall were also reduced (resp.29% and 36%) by PCmAb. PCmAb improved IPA by a significant reduction in neovessel density of 34%. This was supported in vitro by significant reduced EC proliferation and migration upon PCmAB with and without oxLDL stimulation. Moreover, PCmAb enhanced maturation of intraplaque angiogenic vessels by increasing neovessel pericyte coverage in vivo (31%). Together, this resulted in a reduction of IPH of 62% in the PCmAB group. PCmAb resulted in decreased macrophages CD163+ content in vein grafts by 23% whereas CD163 expression was reduced by PCmAb in Hb:Hp stimulated macrophages. Conclusion PCmAB is an effective inhibitor of atherosclerotic lesion formation in ApoE3*Leiden mice. PCmAb reduces IPA and IPH by decreased neovessel density and (CD163+) macrophages influx via reduced expression of VCAM-1 and ICAM-1, and increased neovessel maturation in vein graft atherosclerosis. PCmAB holds a promise as a new therapeutic approach for plaque stability. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Leiden University Medical Center
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Dietz, Matthieu, Christel H. Kamani, Emmanuel Deshayes, Vincent Dunet, Periklis Mitsakis, George Coukos, Marie Nicod Lalonde, Niklaus Schaefer, and John O. Prior. "Imaging angiogenesis in atherosclerosis in large arteries with 68Ga-NODAGA-RGD PET/CT: relationship with clinical atherosclerotic cardiovascular disease." EJNMMI Research 11, no. 1 (August 14, 2021). http://dx.doi.org/10.1186/s13550-021-00815-5.

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Abstract Background Integrin alpha-V-beta-3 (αvβ3) pathway is involved in intraplaque angiogenesis and inflammation and represents a promising target for molecular imaging in cardiovascular diseases such as atherosclerosis. The aim of this study was to assess the clinical correlates of arterial wall accumulation of 68Ga-NODAGA-RGD, a specific αvβ3 integrin ligand for PET. Materials and methods The data of 44 patients who underwent 68Ga-NODAGA-RGD PET/CT scans were retrospectively analyzed. Tracer accumulation in the vessel wall of major arteries was analyzed semi-quantitatively by blood-pool-corrected target-to-background ratios. Tracer uptake was compared with clinically documented atherosclerotic cardiovascular disease, cardiovascular risk factors and calcified plaque burden. Data were compared using the Mann–Whitney U test, Pearson correlation and Spearman correlation. Results 68Ga-NODAGA-RGD arterial uptake was significantly higher in patients with previous clinically documented atherosclerotic cardiovascular disease (mean TBR 2.44 [2.03–2.55] vs. 1.81 [1.56–1.96], p = 0.001) and showed a significant correlation with prior cardiovascular or cerebrovascular event (r = 0.33, p = 0.027), BMI (ρ = 0.38, p = 0.01), plaque burden (ρ = 0.31, p = 0.04) and hypercholesterolemia (r = 0.31, p = 0.04). Conclusions 68Ga-NODAGA-RGD holds promise as a non-invasive marker of disease activity in atherosclerosis, providing information about intraplaque angiogenesis.
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Kolodgie, Frank D., Aya Nakazawa, Saami K. Yazdani, Erica Pacheco, Xin Xu, Qi Cheng, Elena Ladich, and Renu Virmani. "Abstract 512: Infiltrating CD4 Positive T cells may Support an Angiogenic Switch in Human Coronary Atheroma." Circulation 118, suppl_18 (October 28, 2008). http://dx.doi.org/10.1161/circ.118.suppl_18.s_308-d.

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Background: Pathologic angiogenesis has been implicated in the development of high-risk plaques where nascent immature leaky vessels become the primary source of intraplaque hemorrhage contributing to necrotic core expansion. The stage of lesion progression, however, favoring an angiogenic response has not been identified. Methods and Results: Multiple coronary lesions collected from 73 sudden coronary death victims at autopsy were examined. Plaque morphologies included pathologic intimal thickening (PIT), fibroatheromas whose cores were in an early stage (eFA) or late stage (lFA) of necrosis, thin-cap fibroatheromas (TCFA) and ruptures (pR). Lesions were characterized by immunostaining using specific markers directed against endothelial cells (CD31/CD34), smooth muscle cells (α-actin), macrophages (CD68), and T-lymphocytes (CD45RO, CD4). Mean intraplaque vessel densities per mm 2 between lesions with PIT and eFA increased significantly (PIT= 15.84±16.73 vs. eFA= 42.07±40.70, p=0.0054) where maximal numbers of vessels were found in pR (66.57±33.42). Overall, intraplaque vessels associated with actin 3 SMCs, were generally <10%, suggesting a more immature phenotype. Increased vessel densities coincided with greater numbers of inflammatory macrophages and T-cells. Notably, T-cell numbers in areas with high intraplaque vessel densities increased approximate 3-fold between lesions with PIT and eFA (PIT= 62.62±76.50 vs. eFA= 182.33±171.54, p=0.0043) with maximal numbers displayed in TCFAs and pRs, in particular at the intimal/medial border. Populations infiltrating T cells were predominantly CD4 3 and most of these appeared to be activated (human leukocyte antigen DR positive). Conclusion: Atherosclerotic coronary arteries express a latent proangiogenic phenotype coinciding with a localized increased in activated CD4 3 T-cells and early plaque necrosis.
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Hu, Shuhong, Yifei Liu, Tao You, and Li Zhu. "Semaphorin 7A Promotes VEGFA/VEGFR2-Mediated Angiogenesis and Intraplaque Neovascularization in ApoE-/- Mice." Frontiers in Physiology 9 (November 30, 2018). http://dx.doi.org/10.3389/fphys.2018.01718.

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40

Perrotta, Paola, Margreet R. de Vries, Bart Peeters, Pieter-Jan Guns, Guido R. Y. De Meyer, Paul H. A. Quax, and Wim Martinet. "PFKFB3 gene deletion in endothelial cells inhibits intraplaque angiogenesis and lesion formation in a murine model of venous bypass grafting." Angiogenesis, August 25, 2021. http://dx.doi.org/10.1007/s10456-021-09816-3.

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AbstractVein grafting is a frequently used surgical intervention for cardiac revascularization. However, vein grafts display regions with intraplaque (IP) angiogenesis, which promotes atherogenesis and formation of unstable plaques. Graft neovessels are mainly composed of endothelial cells (ECs) that largely depend on glycolysis for migration and proliferation. In the present study, we aimed to investigate whether loss of the glycolytic flux enzyme phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) in ECs inhibits IP angiogenesis and as such prevents unstable plaque formation. To this end, apolipoprotein E deficient (ApoE−/−) mice were backcrossed to a previously generated PFKFB3fl/fl Cdh5iCre mouse strain. Animals were injected with either corn oil (ApoE−/−PFKFB3fl/fl) or tamoxifen (ApoE−/−PFKFB3ECKO), and were fed a western-type diet for 4 weeks prior to vein grafting. Hereafter, mice received a western diet for an additional 28 days and were then sacrificed for graft assessment. Size and thickness of vein graft lesions decreased by 35 and 32%, respectively, in ApoE−/−PFKFB3ECKO mice compared to controls, while stenosis diminished by 23%. Moreover, vein graft lesions in ApoE−/−PFKFB3ECKO mice showed a significant reduction in macrophage infiltration (29%), number of neovessels (62%), and hemorrhages (86%). EC-specific PFKFB3 deletion did not show obvious adverse effects or changes in general metabolism. Interestingly, RT-PCR showed an increased M2 macrophage signature in vein grafts from ApoE−/−PFKFB3ECKO mice. Altogether, EC-specific PFKFB3 gene deletion leads to a significant reduction in lesion size, IP angiogenesis, and hemorrhagic complications in vein grafts. This study demonstrates that inhibition of endothelial glycolysis is a promising therapeutic strategy to slow down plaque progression.
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van der Vorst, Emiel P. C., Sanne L. Maas, Kosta Theodorou, Linsey J. F. Peters, Han Jin, Timo Rademakers, Marion J. Gijbels, et al. "Endothelial ADAM10 controls cellular response to oxLDL and its deficiency exacerbates atherosclerosis with intraplaque hemorrhage and neovascularization in mice." Frontiers in Cardiovascular Medicine 10 (January 27, 2023). http://dx.doi.org/10.3389/fcvm.2023.974918.

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IntroductionThe transmembrane protease A Disintegrin And Metalloproteinase 10 (ADAM10) displays a “pattern regulatory function,” by cleaving a range of membrane-bound proteins. In endothelium, it regulates barrier function, leukocyte recruitment and angiogenesis. Previously, we showed that ADAM10 is expressed in human atherosclerotic plaques and associated with neovascularization. In this study, we aimed to determine the causal relevance of endothelial ADAM10 in murine atherosclerosis development in vivo.Methods and resultsEndothelial Adam10 deficiency (Adam10ecko) in Western-type diet (WTD) fed mice rendered atherogenic by adeno-associated virus-mediated PCSK9 overexpression showed markedly increased atherosclerotic lesion formation. Additionally, Adam10 deficiency was associated with an increased necrotic core and concomitant reduction in plaque macrophage content. Strikingly, while intraplaque hemorrhage and neovascularization are rarely observed in aortic roots of atherosclerotic mice after 12 weeks of WTD feeding, a majority of plaques in both brachiocephalic artery and aortic root of Adam10ecko mice contained these features, suggestive of major plaque destabilization. In vitro, ADAM10 knockdown in human coronary artery endothelial cells (HCAECs) blunted the shedding of lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1) and increased endothelial inflammatory responses to oxLDL as witnessed by upregulated ICAM-1, VCAM-1, CCL5, and CXCL1 expression (which was diminished when LOX-1 was silenced) as well as activation of pro-inflammatory signaling pathways. LOX-1 shedding appeared also reduced in vivo, as soluble LOX-1 levels in plasma of Adam10ecko mice was significantly reduced compared to wildtypes.DiscussionCollectively, these results demonstrate that endothelial ADAM10 is atheroprotective, most likely by limiting oxLDL-induced inflammation besides its known role in pathological neovascularization. Our findings create novel opportunities to develop therapeutics targeting atherosclerotic plaque progression and stability, but at the same time warrant caution when considering to use ADAM10 inhibitors for therapy in other diseases.
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42

Maas, S. L., H. Jin, C. Lu, J. Nagenborg, J. M. H. Karel, R. Cavill, C. J. J. M. Sikkink, et al. "Identification of a PRDM1-regulated T cell network to regulate T cell driving plaque inflammation in human and mouse atherosclerosis." European Heart Journal 43, Supplement_2 (October 1, 2022). http://dx.doi.org/10.1093/eurheartj/ehac544.3049.

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Abstract T cells have a prominent role in the pathogenesis of atherosclerosis, although their exact function remains elusive. Here, we pursued a network-driven approach to identify T cell-associated gene programs driving the transition from low- to high-risk human plaques. In this study 43 human carotid arterial plaques were collected and stratified based on absence (low-risk) or presence (high-risk) of intraplaque haemorrhage (IPH). Lesion RNA was subjected to microarray gene expression analysis and analysed by Weighted Gene Co-expression Network Analysis (WGCNA). We identified a co-expressed gene cluster displaying a strong T cell signalling signature in high- versus low-risk plaque, which was tightly connected to subnetworks of angiogenesis and interferon-signalling. WGCNA-based Bayesian network inference, cell-type deconvolution and single-cell gene expression revealed that this T cell-associated gene program was likely linked to effector-memory cytotoxic CD8+ T cells, underpinning the central role of T cells in plaque destabilization. Gene regulatory analysis identified cytotoxic T cell-related transcription factors, like PRDM1, regulating this plaque T cell gene program. Moreover, we demonstrated in LDL receptor knockout mice with T cell-specific Prdm1 deficiency, that lack of Prdm1 in T cells resulted in larger, more advanced plaques. In conclusion, our study reveals a PRDM1-regulated T cell footprint in high- versus low-risk human atherosclerotic lesions and murine atherosclerotic plaque development, thereby identifying this network as a potential target for intervention in adverse T cell responses. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): The European Research Area Network on Cardiovascular Diseases (ERA-CVD and Dutch Heart Foundation)
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43

Reijrink, M., J. van Ark, C. P. H. Lexis, L. M. Visser, M. E. Lodewijk, I. C. C. van der Horst, C. J. Zeebregts, et al. "Increased frequency of proangiogenic tunica intima endothelial kinase 2 (Tie2) expressing monocytes in individuals with type 2 diabetes mellitus." Cardiovascular Diabetology 21, no. 1 (May 12, 2022). http://dx.doi.org/10.1186/s12933-022-01497-6.

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Abstract Background Individuals with type 2 diabetes mellitus (T2DM) have an increased risk for developing macrovascular disease (MVD) manifested by atherosclerosis. Phenotypically and functionally different monocyte subsets (classical; CD14++CD16−, non-classical; CD14+CD16++, and intermediate; CD14++CD16+) including pro-angiogenic monocytes expressing Tie2 (TEMs) can be identified. Here we investigated monocyte heterogeneity and its association with T2DM and MVD. Methods Individuals with (N = 51) and without (N = 56) T2DM were recruited and allocated to "non-MVD" or "with MVD" (i.e., peripheral or coronary artery disease) subgroups. Blood monocyte subsets were quantified based on CD14, CD16 and Tie2 expression levels. Plasma levels of Tie2-ligands angiopoietin-1 and angiopoietin-2 were determined using ELISA. Carotid endarterectomy samples from individuals with (N = 24) and without (N = 22) T2DM were stained for intraplaque CD68+ macrophages (inflammation) and CD34+ (angiogenesis), as plaque vulnerability markers. Results Monocyte counts were similar between individuals with T2DM and healthy controls (non-diabetic, non-MVD). Non-classical monocytes were reduced (p < 0.05) in T2DM, whereas the percentage of TEMs within the intermediate subset was increased (p < 0.05). T2DM was associated with increased angiopoietin-1 (p < 0.05) and angiopoietin-2 (p = 0.0001) levels. Angiopoietin-2 levels were higher in T2DM individuals with MVD compared with non-MVD (p < 0.01). Endarterectomized plaques showed no differences in macrophage influx and microvessel number between individuals with and without T2DM. Conclusions Monocyte subset distribution is altered in T2DM with reduced non-classical monocytes and increased TEM percentage in the intermediate monocyte subset. Increased angiopoietin-2 levels together with increased frequency of TEMs might promote plaque vulnerability in T2DM which could however not be confirmed at tissue level in advanced atherosclerotic lesions.
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Nanda, Vivek, Kelly Downing, Yoko Kojima, Jessie Dalman, Daniel M. DiRenzo, Andrew J. Connolly, Lars Maegdefessel, et al. "Abstract 38: Cyclin-Dependent Kinase Inhibitor 2B Regulates Transforming Growth Factor Beta 1 Mediated Smooth Muscle Cell Recruitment to Ischemic Blood Vessels." Arteriosclerosis, Thrombosis, and Vascular Biology 35, suppl_1 (May 2015). http://dx.doi.org/10.1161/atvb.35.suppl_1.38.

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Peripheral artery disease (PAD) is a highly morbid condition affecting nearly 8.5 million Americans. Genome wide association studies (GWAS) have identified genetic variation at the chromosome 9p21 cardiovascular risk locus as an important source of heritable PAD risk. However, it is unknown whether this association is secondary to an increase in atherosclerosis or is the result of a separate angiogenesis-related mechanism. Quantitative ultrastructural evaluation of human plaque laden vascular samples revealed that carriers of the 9p21 risk allele displayed a significantly increased burden of immature intraplaque microvessels than carriers of the ancestral allele. To determine whether this process occurs under non-atherosclerotic conditions, we performed femoral artery ligation surgery in mice lacking Cdkn2b; a candidate gene we previously identified to have reduced expression in human carriers of the 9p21 risk allele. These animals developed advanced hind-limb ischemia and digital auto-amputation, relative to wild-type controls. Interestingly, in situ and in vitro hypoxic assays identified this defect to be a consequence of pro-angiogenic behavior displayed by CDKN2B deficient endothelial cells (EC) and impaired smooth muscle cell (SMC) recruitment to the developing neovessel. Exploratory microarray studies performed to identify the mechanism involved, revealed that TGFβ1 signaling is significantly induced in cultured CDKN2B -deficient cells; a finding later confirmed in the vasculature of individuals carrying the 9p21 risk allele. Subsequent molecular signaling studies reveal this increase to be a result of impaired expression of the inhibitory factor, SMAD-7. Increased TGFβ1 signaling was ultimately found to manifest the upregulation of a poorly studied effector molecule, TGFβ1-induced-1, which is a TGFβ-‘rheostat’ known to have antagonistic effects on the EC and SMC. Dual knockdown and rescue studies confirmed the reversibility of the proposed mechanism, in vitro. Taken together these findings suggest that loss of CDKN2B may not only promote cardiovascular disease through the development of atherosclerosis, but may also impair TGFβ1 signaling and hypoxic neovessel maturation consequently resulting in PAD.
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Goncalves, I., C. Tengryd, S. H. Nielsen, F. Genovese, E. Bengtsson, M. Karsdal, D. J. Leeming, J. Nilsson, and A. Edsfeldt. "3046High levels of MMP-cleaved mimecan is associated to carotid plaque stability and less future cardiovascular events." European Heart Journal 40, Supplement_1 (October 1, 2019). http://dx.doi.org/10.1093/eurheartj/ehz745.0013.

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Abstract Introduction The clinical consequences of atherosclerosis, myocardial infarction and stroke are the most common causes of death globally. Mimecan, a small leucine rich-repeat proteoglycan (SLRP), is cleaved by matrix metalloproteinases (MMPs) and known to be involved in collagen fibrillogenesis and angiogenesis. Circulating levels of MMP-cleaved mimecan (cMIM) has previously been identified as a marker of extracellular matrix remodelling in ApoE−/− knockout mice. The role of mimecan and its degradation in human atherosclerotic plaques has not been explored. Purpose We explored whether full-length mimecan and cleaved mimecan (cMIM) are associated to plaque composition and evaluated if they can predict future cardiovascular events. Methods Two hundred and eighteen human atherosclerotic plaques were stained for mimecan using immunohistochemistry. cMIM was measured in 202 plaque tissue homogenates using a competitive ELISA assay. Histological components (α-actin, CD68 and glycophorin A) were assessed using immunohistochemistry, neutral lipids were measured using Oil Red O and visible areas of calcium deposits were quantified. Matrix metalloproteinases (MMP-1, -2, -3, -9, -10 and -12), tissue inhibitors of matrix metalloproteinases (TIMP-1 and -2) were analysed in plaque tissue homogenates using ELISA assays and a proximity extension assay. ECM components (glycosaminoglycans, collagen and elastin) were detected with colorimetric assays and the TGF-β1, β2 and β3 were measured by a multiplex assay. Cardiovascular events were registered using national registers, patient records and telephone calls during a follow-up period of 59 months IQR (34–73). Results Mimecan was expressed in human atherosclerotic plaques. The expression correlated positively with neutral lipids and intraplaque hemorrhage and inversely with α-actin. In contrast cMIM correlated with α-actin and inversely with neutral lipids. cMIM correlated also with stabilizing extracellular matrix proteins elastin, collagen as well as TGF-β1, β2 and β3. Mimecan correlated to MMP-9 and cMIM correlated to MMP-2 and TIMP-2. Patient with high levels of cMIM had a lower risk of future cardiovascular events which remained significant after adjusting for risk factors (age, gender, diabetes and symptoms) in a multivariate Cox regression Conclusion(s) Mimecan was associated with vulnerable plaque features, whereas cMIM was related to stable plaque features. Low levels of cMIM predicted future cardiovascular events, independently of known risk factors. Taken together this suggests a possible role for mimecan and its cleavage in atherosclerosis that needs to be further explored. Acknowledgement/Funding Danish Research Foundation, Swedish Research Council, Swedish Heart and Lung Foundation, Skåne University Hospital and more.
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