Academic literature on the topic 'Lymphatic vascular remodelling'

The lymphatic system is important for return of extra-vascular fluid to the blood circulation, conductance of hormones and immune cell trafficking. Delicate hormonal control of fluid conductance during reproductive cycles is exemplified by the ovarian hyperstimulation syndrome, a dangerous condition of hypovolemia caused by fluid accumulation in the abdomen and reproductive tissues, in response to hormonal hyperstimulation. This study is the first to investigate the relationship between ovarian lymphatic development and follicle growth. Quantitative morphometric analysis of vessel size and number in mouse ovary revealed, for the first time, that the ovarian lymphatic vasculature develops postnatally and in synchrony with the induction of ovarian CYP19a1 (Aromatase); the time when secondary follicles become FSH-responsive and estrogenic. Mechanistically, we found that the FSH-analogue eCG mediates induction of lymphatic vascular endothelial growth factor Vegfd and the receptor Vegfr3 (Flt4) in granulosa cells. Importantly, stimulation with eCG also enhanced ovarian lymphatic vessel number and size. However, formation of ovarian lymphatics also required the matrix-remodelling protease Adamts1, since ovaries from Adamts1−/− mice failed to undergo normal lymphatic vascular development. Treatment of Adamts1 null mice with eCG significantly increased the number and size of ovarian lymphatic vessels, however, the vessels were still smaller and fewer in number than wildtypes. These combined results indicate that the ovarian lymphatic system develops in response to hormonal signals, which promote folliculogenesis, through induction of lymphangiogenic factors in granulosa cells; as well as involving Adamts1-dependent mechanisms. This study is the first demonstration of the novel principle of hormonal regulation of lymphangiogenesis in any tissue and suggests a requirement for functional lymphatics during normal folliculogenesis. In addition our results inform the elucidation of the tightly regulated processes that control fluid dynamics and immune cell surveillance within reproductive tissues.

Angiogenesis, lymphangiogenesis and vascular maturation occur on a regular, physiological basis in human endometrium. These processes form part of a continuum of vascular remodelling involving numerous regulatory factors. Key factors include vascular endothelial growth factor (VEGF)A, VEGFC and VEGFD, and their associated receptors VEGFR1, VEGFR2 and VEGFR3. A second group of vascular regulatory proteins belongs to the angiopoietin (ANG)–TIE system. Although members of the VEGF family and the ANG–TIE system are represented in the endometrium, our understanding of how these different molecules interact to regulate remodelling of the blood and lymphatic vasculature present in the endometrium is still limited. A review of the current information is provided.

The mammalian placenta plays central roles in maternal tolerance of the semi-allogeneic fetus and fluid balance between maternal and fetal compartments. The lymphatics play a role in both immune function and fluid balance. The aim of this study was to describe the distribution of lymphatic vessels in human placental bed and decidua, with particular focus on the lymphatics that surround the remodelling spiral arteries during decidualisation and trophoblast invasion. Placental bed, non-placental bed and decidual biopsies were obtained from women undergoing elective pregnancy termination (6–18 weeks gestational age) and from women undergoing elective caesarean section at term. Double immunohistochemical labeling was performed on serial sections to identify lymphatic vessels in conjunction with blood vessels, smooth muscle, epithelial and trophoblast cells, or proliferating cells. Using representative photomicrographs, descriptive findings of the organisation of the human placental bed lymphatics were made. Lymphatic vessels positive for podoplanin (D2-40) were abundant in hypersecretory endometrium (lacking stromal decidualisation) at all stages of gestation. By contrast, the decidua was nearly always devoid of lymphatics. In some samples, structures that appeared to be regressing lymphatics were observed at the boundary between hypersecretory and decidual tissues. Lymphatic vessels were notably absent from the vicinity of spiral arteries that were surrounded by decidualised stromal cells. Lymphatic vessels in hypersecretory endometrium appeared larger and more elongated as gestation progressed. Proliferating lymphatic vascular endothelial cells were identified in both large vessels, and in streaks of D2-40 positive cells that could have been newly forming lymphatic vessels. In conclusion endometrial stromal cell decidualisation results in a loss of lymphatics, with this phenomenon being particularly apparent around the spiral arterioles; the functional consequences of this loss have yet to be elucidated.

Endothelial cells that form the inner layer of blood and lymphatic vessels are important regulators of vascular functions and centrally involved in the pathogenesis of vascular diseases. In addition to the vascular endothelial growth factor (VEGF) receptor pathway, the angiopoietin (Ang)–Tie system is a second endothelial cell specific ligand–receptor signalling system necessary for embryonic cardiovascular and lymphatic development. The Ang–Tie system also regulates postnatal angiogenesis, vessel remodelling, vascular permeability and inflammation to maintain vascular homoeostasis in adult physiology. This system is implicated in numerous diseases where the vasculature has an important contribution, such as cancer, sepsis, diabetes, atherosclerosis and ocular diseases. Furthermore, mutations in the TIE2 signalling pathway cause defects in vascular morphogenesis, resulting in venous malformations and primary congenital glaucoma. Here, we review recent advances in the understanding of the Ang–Tie signalling system, including cross-talk with the vascular endothelial protein tyrosine phosphatase (VE-PTP) and the integrin cell adhesion receptors, focusing on the Ang–Tie system in vascular development and pathogenesis of vascular diseases.

Postprandial (PP) lipaemia is a significant contributor to the development of dyslipidaemia and cardiovascular disease (CVD). It is also evident that PP lipaemia is prevalent during conditions of obesity and insulin resistance (IR) and may contribute to increased progression of CVD. Our group has assessed the potential of the obese JCR:LA-cp rat as a model of PP lipaemia in order to explore CM (chylomicron) metabolism during the onset and development of IR in the metabolic syndrome. Studies confirm that both fasting plasma and PP apoB48 (apolipoprotein B48) area under the curve are significantly elevated in the obese JCR:LA-cp phenotype as compared with lean controls. Mechanistic studies have also shown that the concentration of lymphatic CM apoB48 and CM size are significantly increased in this model. Furthermore, PP dyslipidaemia in the obese rat can be improved acutely with supplementation of n−3 polyunsaturated fatty acids. Using a different approach, we have subsequently hypothesized that the vascular remodelling that accompanies IR may explain accelerated entrapment of apoB48-containing particles. Small leucine-rich proteoglycans (including biglycan and decorin) have been observed to co-localize with apoB in human tissue. However, the potential impact of IR on vascular remodelling, particularly in the presence of obesity, remains unclear. Preliminary observations from the JCR:LA-cp model indicate that biglycan protein core content increases with age and is exacerbated by IR, suggestive of pro-atherogenic remodelling. The focus of this review is to contribute to the perspective of PP lipaemia in CVD risk associated with the metabolic syndrome through the use of animal models.

The lymphatic system is a vascular system comprising modified lymphatic endothelial cells, lymph nodes and other lymphoid organs. The system has diverse, but critical functions in both physiology and pathology, and forms an interface between the blood vascular and immune system. It is increasingly evident that remodelling of the lymphatic system occurs alongside remodelling of the blood microvascular system, which is now considered a hallmark of most pathological conditions as well as being critical for normal development. Much attention has focussed on how the blood endothelium undergoes phenotypic switching in development and disease, resulting in over two decades of research to probe the mechanisms underlying the resulting heterogeneity. The lymphatic system has received less attention, and consequently there are fewer descriptions of functional and molecular heterogeneity, but differential transcription factor activity is likely an important control mechanism. Here we introduce and discuss significant transcription factors of relevance to coordinating cellular responses during lymphatic remodelling as the lymphatic endothelium dynamically changes from quiescence to actively remodelling.

Background: Diabetes is associated with a significantly elevated risk of heart failure. However, the precise cellular and molecular protagonists underpinning the development of heart failure in diabetes remains unclear. Moreover, very little is known, of how disparate non-myocyte populations of the heart contribute to diabetic cardiomyopathy. Methodology: To address this gap in knowledge, we conducted single-cell transcriptomic analysis of non-myocytes from heart ventricles of spontaneous type-2 diabetic ( db/db ) male mice. Findings were corroborated by flow cytometry, histology and computational analysis of publically available bulk RNA sequencing datasets from alternative diabetes models. Results: Single-cell transcriptomic analysis of db/db mouse hearts revealed a concerted diabetes-induced cellular response driving cardiac pathological remodelling. We identified diabetes-induced up-regulation of pathways contributing to known features of diabetic cardiomyopathy such as dysregulation of vascular homeostasis and lipid metabolism, as well as augmented inflammation, in cell specific contexts. We also identified unexpected characteristics in the diabetic heart, including impaired protein folding and cellular trafficking within lymphatic vessels. Using flow cytometry and histology, increase in inflammatory cells, such as Ly6C hi monocytes, shifts in macrophage phenotype, and increased abundances of fibroblasts and endocardial cells were confirmed. Finally, integration of single-cell transcriptomic data with publically available bulk-RNA sequencing datasets from alternative diabetes models revealed shared hallmarks of diabetic heart and disease context-dependent features. Conclusions: Together, this work offers a new perspective for understanding the cellular and molecular mediators of diabetes-induced cardiac pathology. Targeting these mediators may offer new therapeutic avenues to address the cardiac complications associated with diabetes.

The lymphatic vasculature, an essential component of the cardiovascular system, serves several functions critical to embryonic development and adult homeostasis. Lymphatic vessels return interstitial protein-rich fluid to the bloodstream, transport immune cells during immune surveillance and infection and absorb lipids from the digestive tract (Alitalo et al., 2005; Tammela and Alitalo, 2010). The aberrant growth and development of lymphatic vessels (lymphangiogenesis) is a common feature of human disorders including lymphoedema, inflammatory diseases and tumour metastasis (Alitalo et al., 2005; Tammela and Alitalo, 2010). Lymphatic vessels are of key importance to breast cancer patients. Lymphatic vessels are exploited as a key route of metastasis for tumour cells and the ability of a tumour to promote lymphangiogenesis has been linked with metastasis and poor patient prognosis (Gu et al., 2008; Nakamura et al., 2005; Nakamura et al., 2003; Ran et al., 2010; Skobe et al., 2001). Moreover, lymphatic vascular damage incurred during the surgical resection of lymph nodes commonly results in secondary lymphoedema, a debilitating complication for up to 40% of breast cancer patients (Armer et al., 2009). Despite the involvement of lymphatic vessels in breast cancer, the genes and molecular mechanisms that regulate lymphangiogenesis in the breast remain relatively uncharacterised. The mammary epithelium and blood vasculature undergo dynamic remodelling events in response to hormonal signals and functional demands during postnatal mouse mammary gland morphogenesis (Djonov et al., 2001; Matsumoto et al., 1992; Richert et al., 2000; Watson and Khaled, 2008). The aims of this project were: 1. To investigate the spatial organisation of lymphatic vessels in the mouse mammary gland. 2. To investigate whether lymphatic vessels, like blood vessels and the mammary epithelial tree, are temporally remodelled during mouse mammary gland morphogenesis. 3. To define signals that regulate lymphangiogenesis during postnatal mouse mammary gland morphogenesis. This study provides the first evidence demonstrating that the lymphatic vasculature is dynamically remodelled along with the mammary epithelial tree and blood vasculature during postnatal mouse mammary gland morphogenesis. In addition, this study reveals an intimate association of lymphatic vessels with epithelial ducts, a finding that has important implications for tumour metastasis, as well as the spatial organisation of lymphatic vessels in other branched epithelial tissues, including the lung, kidney, pancreas and prostate. Furthermore, we established that vascular endothelial growth factor (Vegf) C (Vegfc) and Vegfd mRNA levels are significantly increased early during pregnancy and that proteolytically-processed, active VEGF-D is expressed selectively in pregnant, but not virgin mouse mammary glands, corresponding with the stage of peak lymphatic vessel density. In accordance with these data, we demonstrated that a tyrosine kinase inhibitor specific for VEGF receptor 3 (Kirkin et al., 2001; Kirkin et al., 2004), the principal receptor for mouse VEGF-C and VEGF-D, can block the proliferation of primary dermal lymphatic endothelial cells that is stimulated by mammary epithelial and stromal cell conditioned media ex vivo. These data suggest that VEGF-C and VEGF-D, two of the best characterised lymphangiogenic stimuli to date, are likely to play key roles in the stimulation of lymphangiogenesis in the pregnant mouse mammary gland. Elucidation of the molecular mechanisms controlling lymphangiogenesis in the mammary gland has the potential to reveal important targets for the future generation of pro- and anti-lymphangiogenic therapeutics, with the ultimate goal to repair surgically damaged lymphatic vessels and prevent breast cancer metastasis, respectively.
Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2011

Both are routine questions encountered by students during their time in dental school, and both require sound knowledge of the anatomy of the head and neck. From wrestling with basic anatomical concepts and planes to tracing the branches of the external carotid artery, anatomy will underpin the rest of your practising career and is a fundamental building block on which all other knowledge can be laid down. Basic ana­tomical knowledge begins with the osseous structures of the head and neck, blood vessels, lymphatics, and nerves. Interpretation of this know­ledge is required for functional and clinical applications, which is a daily occurrence for practising dentists and dental care professionals. Such a large subject is difficult to assess in a small number of questions, but this chapter touches on aspects of developmental embryology and tooth formation, along with functional anatomical questions designed to test the theory behind some common dental procedures and clinical presen­tations. Undoubtedly, excellent knowledge of the innervation and blood supply to the teeth and surrounding structures will be most beneficial for dentists and dental care professionals during their practising careers. Key topics include: ● Anatomical planes and terminology ● Craniofacial development ● The musculoskeletal system, including ossification and bony remodelling ● Innervation and vascular supply to the head and oral cavity, including the cranial nerves ● Structure of the eye, ear, nasal cavity, and oral cavity ● Odontogenesis ● Histology of the oral cavity.