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1
Holmén, Carolina. "Mechanisms of endothelial cell dysfunction in Wegener's granulomatosis /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-443-0/.
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Clayton, Zoe Ellen. "The pro-angiogenic properties of induced pluripotent stem cell derived endothelial cells and induced endothelial cells." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17300.
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Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, (1, 2). Current interventions are ineffective in up to 30% of patients due to the presence of diffuse or extensive atherosclerosis, therefore the development of alternative or supplementary therapies for CVD is a high priority for medical research. Therapeutic angiogenesis, enhancing the growth of new blood vessel networks from the existing vasculature, is a promising strategy for restoring blood flow to ischaemic tissue. Stem cells have shown potential as pro-angiogenic therapies for patients with coronary artery disease (CAD) and peripheral artery disease (PAD). Induced pluripotent stem cells (iPSCs) can be derived from plentiful sources of adult somatic cells, such as dermal fibroblasts (3, 4). Human iPSCs have been differentiated to endothelial cells (iPSC-ECs) and, more recently, induced endothelial cells (iECs) have been generated by direct differentiation of fibroblasts, which bypasses the pluripotent intermediate (5-11). IPSC-ECs and iECs have potential advantages over other cell types in that they can be generated in large quantities, they are not of embryonic origin and they have minimal immunogenicity. Endothelial cells have been produced via many different reprogramming and differentiation protocols, but little work has been done to determine which of these methods generates populations of cells with the greatest therapeutic potential. The studies presented in this thesis show that both iPSC-ECs and iECs have endothelial functionality in vitro and can enhance ischaemia mediated angiogenesis in a murine model of PAD. Our findings suggest that iPSC-ECs may be the more robust cell type as they demonstrate superior survival and engraftment potential in vivo. We have also generated novel data showing that iPSC-ECs enhance wound perfusion, increase wound collagen content and accelerate wound closure, which suggests they are a promising candidate therapy for chronic wounds and diabetic ulcers. Overall, the work presented in this thesis provides evidence to support the development of clinical-grade iPSC-ECs and iECs for therapeutic angiogenesis in cardiovascular disease settings.
3
Harrison, Vanessa Jane. "The characterisation of endothelin-converting enzyme in endothelial cells." Thesis, Queen Mary, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307673.
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Ristori, Emma. "Vascular Endothelial Growth Factors and Endothelial Cells Behaviour." Doctoral thesis, Università di Siena, 2021. http://hdl.handle.net/11365/1127960.
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L'endotelio vascolare è un importante tessuto il cui ruolo sia in fisiologia, che in patologia è stato a lungo sottovalutato. Per molti anni, l'inaccessibilità di questo tessuto ha reso difficoltoso valutarne il ruolo fisio-patologico.
La disfunzione delle cellule endoteliali è alla base di molti se non tutti gli stati patologici e può manifestarsi a diversi livelli dello sviluppo vascolare: durante la vasculogenesi, durante il processo di angiogenesi oppure durante il rimodellamento vascolare. Il processo di vasculogenesi consiste nella specializzazione di precursori vascolari in arterie e vene. Il termine angiogenesi si riferisce invece alla formazione di nuovi vasi sanguigni a partire da vasi preesistenti. Il processo è attivato da fattori pro-angiogenici che promuovono la migrazione e proliferazione delle cellule endoteliali e l'anastomosi dei vasi neoformati. In seguito, i nuovi vasi subiranno rimodellamenti secondari, come la regressione di particolari capillari, per formare un network vascolare maturo e funzionale.
I fattori di crescita endoteliali vascolari (VEGFs) svolgono un ruolo cruciale, sia durante il processo di vasculogenesi e angiogenesi, che nel mantenimento della funzionalità vascolare. La trasduzione del segnale attivata dai VEGFs è complessa. La risposta intracellulare è attivata dal legame dei VEGFs con specifici recettori di membrana (VEGFRs). L'intensità e la durata del segnale sono invece modulate dal legame dei VEGFs con co-recettori e dall'interazione del complesso VEGF/recettore con chinasi, fosfatasi e altre proteine coinvolte nel trasporto del complesso all'interno della cellula.
L'angiogenesi e l’integrità dei vasi sono processi fisiologici strettamente controllati. Infatti, un'angiogenesi non controllata e la perdita d’integrità di membrana con l’aumento di permeabilità portano a disfunzione vascolare e conseguenze patologiche.
Negli ultimi anni, la disfunzione vascolare e l'alterazione del signalling del VEGF nel tessuto vascolare sono state associate all'insorgenza di numerose malattie neurodegenerative, incluso l'Alzheimer (Review I).
Recenti studi suggeriscono un importante ruolo della β-amyloid precursor protein (APP), proteina chiave nello sviluppo della malattia di Alzheimer, nel mantenimento dell'omeostasi cellulare nel cervello, tuttavia la funzione di questa proteina a livello vascolare e la sua interazione con il signalling del VEGF sono tuttora ignote (Review II).
In questo lavoro di tesi ho esaminato il ruolo di APP nella regolazione e modulazione del signalling VEGFA/VEGFR2 e nel mantenimento della funzionalità vascolare (Paper I).
Ho inoltre studiato il ruolo del signalling di VEGF nel differenziamento di arterie e vene durante lo sviluppo vascolare embrionale utilizzando il modello in vivo di zebrafish (Paper II).
Il mio lavoro di ricerca ha contribuito ad ampliare la conoscenza sulla complessa modulazione del signalling di VEGF nel tessuto vascolare, sia durante lo sviluppo embrionale, che durante l'omeostasi vascolare.<br>The vascular endothelium is an important tissue often underestimated for its role in health and disease. Endothelial cells dysfunction is at the base of many if not all diseases. The inaccessibility of this tissue made difficult its assessment for many years.
Vascular dysfunction can occur at different levels of vascular development and maintenance: during initial vasculogenesis, angiogenesis and late vascular remodelling. Vasculogenesis denotes the early developmental process of artery-veins specification. Angiogenesis refers to the formation of new blood vessels from pre-existing quiescent vessels. The angiogenic process is initiated by pro-angiogenic factors that induce endothelial cell sprouting, migration and vascular anastomosis. Newly formed vascular networks undergo extensive vascular remodelling, that includes distinct processes of vascular pruning and regression of selected vascular branches, to form a functional and mature quiescent vasculature.
Vascular endothelial growth factors (VEGFs) are critical players in artery specification during development, in angiogenesis and in vascular maintenance. VEGFs bind to transmembrane VEGFRs receptors to initiate the intracellular response. The VEGF-VEGFR signalling pathway activation and regulation are very complex. In fact, the binding of the ligand VEGF to the VEGFRs receptor is not the only event involved in the activation and regulation of the signalling cascade. Co-receptors, kinases, phosphatases, and other proteins involved in the intracellular trafficking of the VEGF-VEGFR complex modulate the signal specificity, amplitude and duration.
Angiogenesis and vessels stability are tightly regulated physiological processes. Indeed, excessive angiogenesis and increased permeability lead to vascular dysfunction and the progression of several diseases. In the recent years, neurodegenerative diseases such as Alzheimer’s disease have been strongly associated to vascular dysfunction (Review I) and to VEGF/VEGFR2 aberrant signalling. Recent studies suggest an important role of the AD-related β-amyloid precursor protein (APP) in maintaining cellular homeostasis in the brain, however the role of this protein in endothelial cells and its interactions with the VEGF signalling is still unknown (Review II).
In this thesis work, I have examined the role of APP in regulating VEGF/VEGFR2 signalling and endothelial cells stability (Paper I).
Furthermore, I have investigated the in vivo role of VEGF mediated signalling in artery specification during zebrafish vascular development (Paper II).
In conclusion, VEGF mediated signalling is regulated by a multifactor system and each individual regulatory mechanism leads to a specific outcome in angiogenesis and vessel stability.
5
Huang, Lan. "Endothelial Colony Forming Cells (ECFCs): Identification, Specification and Modulation in Cardiovascular Diseases." Thesis, Connect to resource online, 2009. http://hdl.handle.net/1805/2063.
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Thesis (Ph.D.)--Indiana University, 2009.<br>Title from screen (viewed on February 2, 2010). Department of Biochemistry and Molecular Biology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Mervin C. Yoder, Jr., David A. Ingram, Jr., Lawrence A. Quilliam, Mark D. Pescovitz. Includes vitae. Includes bibliographical references (leaves 171-194).
6
Leskinen, Markus. "Mast cell-mediated apoptosis of smooth muscle cells and endothelial cells." Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/leskinen/.
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Altalhi, Wafa. "Biological Effects of Osteopontin on Endothelial Progenitor Cells." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20280.
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Endothelial Progenitor Cells (EPCs) are thought to participate in the healing of injured vascular endothelium by incorporating into the defect sites to mediate endothelial recovery. Recently, osteopontin (OPN) was shown to be fundamental in accelerating estrogen-dependent healing of injured blood vessels. Here, we are investigating the effect OPN has on EPC behavior. Late outgrowth human EPCs (LEPCs) were derived from circulating monocytes isolated by leukophoresis, and grown in culture until passage six. L-EPCs were then assayed for adhesion, spreading, chemotaxis, and haptotaxis, as well as resistance to detachment by flow electric cellsubstrate
impedance sensing (ECIS). The results of standard and ECIS methods showed both dose and time dependent responses in cell adhesion and spreading. In addition, OPN promoted haptotactic migration of EPCs in Boyden chamber assays. LEPCs seeded onto 10μM OPN substrates and exposed to laminar flow had grater survival and higher resistance to detachment than OPN/static and flow only conditions. CD44 and !1 integrins were only responsible for approximately 50% of LEPCs
adhesion to OPN compared to the unblocked condition. Western blots showed that Rho GTPases were activated in L-EPCs seeded on OPN. However, this activation could not be completely blocked by either CD44 or !1 integrin antagonists. These data confirm the direct effects of OPN on EPCs adhesion, and suggest that OPN works by mediating cell adhesion during vascular injury.
8
Zhu, Jing. "The role of nonmuscle myosin IIA in endothelial cell." Morgantown, W. Va. : [West Virginia University Libraries], 2010. http://hdl.handle.net/10450/11006.
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Thesis (M.S.)--West Virginia University, 2010.<br>Title from document title page. Document formatted into pages; contains viii, 37 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 33-37).
9
Prahst, Claudia. "Neuropilin-vascular endothelial growth factor signaling in endothelial cells." [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:25-opus-51230.
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Yang, Weidong. "Oxidative damage of endothelial cells." Thesis, University of Leicester, 1999. http://hdl.handle.net/2381/29603.
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This study sought to investigate the consequences of different degrees of oxidative stress on endothelial cells, using a cultured endothelial cell model; principally bovine aortic endothelial cells, subjected to oxidative stress. High concentrations of H2O2 or a superoxide generating system caused rapid endothelial cell death, as evidenced by increased membrane permeability, which could be partially protected by myoglobin. Extracellular H2O2 caused a rapid increase in intracellular peroxidation but was also eliminated by endothelial cells. However, the anti-oxidant capacity of the bovine endothelial cells was very weak and could be overcome by as little as 5 femtomol hydrogen peroxide per cell. The effects were directly related to the amount of H2O2 available to each cell, rather than the concentration. Exposure to relatively low amounts of H2O2 (<0.5 picomol/cell) led to reduced endothelial cell function including prostacyclin production and mitochondrial dehydrogenase activity, and inhibited cell migration and proliferation. The cells showed gradual, partial recovery from these damaging effects. At low amounts (0.1 to 0.5 picomol/cell) H2O2 induced endothelial cell apoptosis within 48 hours of the exposure. After this time, some of the surviving cells showed evidence of senescence and could remain in culture for up to 30 days. Senescence was accompanied by an increase in cytoplasmic volume and accumulation of lipofusion. Investigation of -galactosidase activity suggested that the increased enzyme expression was linked to cell cycle rather than senescence. In conclusion, endothelial cells are very sensitive to oxidative damage but the nature of the damage is related to the degree of oxidative stress. The effects of oxidative stress may play an important role in atherosclerotic and cardiovascular diseases.
11
Dauphinee, Shauna Marie. "Lipopolysaccharide signaling in endothelial cells." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/23033.
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The endothelium plays a critical role in coordinating the innate immune response through the regulation of vascular tone, leukocyte recruitment and transmigration, and hemostasis. These functions are mediated, in part, by the signaling cascades initiated upon recognition of bacterial and viral products by a family of transmembrane receptors known as Toll-like receptors (TLRs). In endothelial cells, exposure to lipopolysaccharide (LPS), a major cell wall constituent of Gram negative bacteria, results in endothelial activation through TLR4. Recruitment of the adapter protein, MyD88, to the receptor facilitates association of serine threonine kinases of the IL-1 receptor associated kinase (IRAK) family. The IRAKs initiate a phosphorylation cascade through TNFR-associated factor 6 (TRAF6) culminating in activation of proinflammatory signaling pathways including NF-κB and c-Jun NH2-terminal kinase (JNK) pathways. This thesis investigates signaling molecules and pathways downstream of TLR4 in endothelial cells. Specifically, contained herein is a description of the role of heterotrimeric G proteins in endothelial TLR signaling. This thesis identifies for the first time the function of these proteins in multiple TLR signaling pathways. In addition, the work presented here describes the identification and characterization of a novel TLR4 signaling molecule, SAM and SH3 domain containing protein 1 (SASH1). SASH1 promotes LPS-induced NF-κB and JNK, by functioning as a scaffold molecule to bind TRAF6, transforming growth factor-β-activated kinase (TAK1) and IκB-kinase (IKK), thereby increasing proinflammatory cytokine production. The distinct functions of the endothelium in innate immunity highlight the need for an understanding of the signaling cascades initiated by LPS in endothelial cells and will be crucial to our understanding of the pathophysiology of sepsis in the clinic.
12
Zhou, Zhigang. "TNF signalling in endothelial cells." Thesis, University of East Anglia, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435077.
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Pleiotropic cytokine tumour necrosis factor a (TNF) is the archetypal member of a large super-family of ligands and associated receptors. Through its two surface presenting receptors, TNFRI and TNFR2, TNF can elicit responses such as differentiation, proliferation, and apoptosis, depending on several factors such as microenvironment, cell cycle, and cell type. Recent evidence indicated that TNF can be up-regulated in endothelial cells (EC) upon their stimulation and plays an important role in regulating EC responses which have been implicated in several cardiovascular diseases, such as heart failure and atherosclerosis. Anti-TNF therapy has been successfully applied on several inflammatory related diseases, such as rheumatoid arthritis and Crohn's disease. Conversely, for heart failure patients, anti-TNF therapy has been considered but has been disappointing in trials thus far. Therefore, a greater understanding of TNF's ability to signal disparate responses is essential for the development of more effective TNF- or signalling-based therapeutics. Here we demonstrate that the regulation of TNF activity in endothelial cells is controlled by two distinct receptor signalling pathways via its associated adaptor and downstream effector proteins, cross-linked by potential crosstalk mechanisms at different cascades. Our findings clearly demonstrate that TNF activates both the canonical and non-canonical NF-KB pathways, mainly through TNFRI signalling while TNFR2-driven NF-KB nuclear translocation is mainly inhibitory. TNF regulated NF-KB dependent genes including adhesion molecules which were up-regulated via the TNFRI receptor pathway; MAPKs activation may interact with TNF-driven signal at several cascades for fine tuning of its overall effects. We also discovered that TNFR2 is able to switch on survival signals via induction of the protective genes heme oxygenase-1 (HO-1) and ferritin or through the auto-regulation of TNFR2 itself. Through our findings, we hypothesised that TNF elicits in EC its pro-inflammatory effects mainly through TNFRI while balancing the overall signalling response by the survival signals mediated via TNFR2. Our results have implications for improving anti-TNF therapeutic strategies by selective inhibition of TNF receptor signalling rather than inhibiting TNF as a whole.
13
Vickers, James. "Endothelial cells and platelet function." Thesis, University of Nottingham, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336951.
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Fitchett, Caroline Jane. "Lysophosphatidate signalling in endothelial cells." Thesis, University of Wolverhampton, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252450.
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Philippeos, Christina. "Insulin signalling in endothelial cells." Thesis, King's College London (University of London), 2014. http://kclpure.kcl.ac.uk/portal/en/theses/insulin-signalling-in-endothelial-cells(8e35db48-dc9c-41be-b1aa-1fbe241fc356).html.
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Insulin is known to act as an anti-inflammatory agent and protect vascular endothelial cells during ischaemic damage in vivo. Although it is known that insulin signals in part through phosphatidylinositol 3-kinases (PI3Ks) and Akt, its effects on endothelial junctions and actin cytoskeleton are unknown. This study aimed to characterise endothelial responses to insulin, identify endothelial insulin-‐induced changes in protein phosphorylation and determine the roles of these changes in regulating endothelial functions. Insulin stimulation induced dose-dependent Akt activation in both primary human umbilical vein endothelial cells (HUVECs) and an endothelial cell line, human bone-marrow endothelial cells (HBMECs). Insulin decreased basal HUVEC permeability, increased angiogenic loop formation in vitro and increased cell migration in a wound-healing model, compared to untreated cells. Insulin-stimulated changes in protein phosphorylation were identified using a 14-3-3 affinity purification proteomic screen, as 14-3-3 proteins interact specifically with phosphorylated Ser/Thr residues within 14-3-3-binding motifs. A total of 390 14-3-3-binding proteins were identified from insulin-stimulated HBMECs, from which 12 proteins were selected based on predicted roles in endothelial cytoskeleton regulation. Validation of these hits, performed by Far-Western overlay analysis, identified 4 IGF-I-regulated 14-3-3-binding proteins: Parg1 (ARHGAP29), RICH-1 (ARHGAP17), LMO7 and Epsin2. Parg1 depletion in HUVECs induced stress fibre formation, increased endothelial permeability, severely decreased angiogenic loop formation and decreased cell migration, compared to siRNA control-treated cells. This suggests that Parg1 regulates contractility and hence could affect endothelial cell-cell junctional stability. Depletion of RICH-1 and LMO7 in HUVECs resulted in mislocalisation of the tight junction protein ZO-1. However, this did not affect endothelial permeability, suggesting that these proteins are important for maintaining tight junction integrity. LMO7 and Epsin2 depletion each resulted in an increase in angiogenic loop formation, but did not detectably affect cell migration. Insulin stimulation of Epsin2 might increase lamellipodium formation, although further studies are required to establish the mechanisms involved. In conclusion, this thesis describes a 14-3-3-based proteomic screen that identified novel regulators of endothelial function. These proteins could contribute to the anti-inflammatory roles of insulin.
16
McHenry, S. M. "Synergistic interactions between osteoblast cells and endothelial cells." Thesis, Queen's University Belfast, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403243.
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Rabodzey, Aleksandr. "Flow-induced mechanotransduction in cell-cell junctions of endothelial cells." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/41586.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2006.<br>Includes bibliographical references (leaves 86-92).<br>Endothelial cells show an unexpected behavior shortly after the onset of laminar flow: their crawling speed decreases ~40% within the first 30 min, but only in a confluent monolayer of endothelial cells, not in subconfluent cultures, where cell-cell interactions are limited. This led us to study early shear effects on cell-cell adherens junctions. We found a 30±6% increase in the number of VE-cadherin molecules in the junctions. The strength of interactions of endothelial cells with surfaces coated with recombinant VE-cadherin protein also increased after laminar flow. These observations suggest that endothelial cell junction proteins respond to flow onset. The process of clustering may induce diffusion of monomers to the junction area, resulting in an overall increase in VE-cadherins in the junctions. To directly confirm the role of adherens junctions in the decrease in cell crawling speed, we used siRNA-knockdown technique to produce cells lacking VE-cadherin. These cells showed no decline in crawling speed under flow. Our interpretation is consistent with previous data on junction disassembly 8 hr after flow onset. The speed of endothelial cell crawling returns to the original level by that time, and junctional disassembly may explain that phenomenon. In order to understand better the change in VE-cadherin distribution under flow and during junction formation and remodelling, we developed a mathematical model of VE-cadherin redistribution in endothelial cells. This model allowed us to develop a quantitative framework for analysis of VE-cadherin redistribution and estimate the amount of protein in the junctions and on the apical surface. In addition to that, the model explains rapid junction disassembly in the leukocyte transmigration and junction formation in subconfluent cells.<br>(cont.) These studies show that intercellular adhesion molecules are important in the force transmission and shear stress response. Their role, however, is not limited to flow mechanotransduction. Intercellular force transmission has an important application - organ development and, specifically, angiogenesis. We studied the role of VE-cadherin in vessel development in HUVECs and showed that VE-cadherin-null cells do not form vessels in the in vitro assay. This observation confirms the important role of intercellular force transmission in response to external force caused by flow or exerted by other cells.<br>by Aleksandr Rabodzey.<br>Ph.D.
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Skinner, Elizabeth Mary. "Pluripotent stem cell-derived endothelial cells for vascular regeneration." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/15865.
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Background: Vascular endothelial dysfunction plays a major role in the pathogenesis of atherosclerosis. As such, the study of endothelial cells has sought to identify causal pathways and novel therapeutic approaches to promote vascular repair. Induced pluripotent stem (iPS) cell technology may be a particularly useful tool, and could be used to derive endothelial cells and their progenitors from individuals with endothelial dysfunction to explore these pathways and develop novel strategies for vascular regeneration. Whilst iPS cells are conventionally obtained from the reprogramming of dermal fibroblasts, it was hypothesised that endothelial cells could also be reprogrammed, and that these pluripotent cells would have enhanced capacity for endothelial differentiation and vascular regeneration. Objectives: To generate iPS cells from human fibroblasts and endothelial cells and to assess their potential for endothelial differentiation and vascular regeneration. Methods and Results: A) Reprogramming: Dermal fibroblasts and endothelial outgrowth cells from blood were obtained from healthy donors (n=5) and transfected with episomal vectors containing six reprogramming factors: Sox2, Klf4, Oct3/4, L-Myc, Lin28 and Shp53. Successfully reprogrammed fibroblast-derived iPS (fiPS) and endothelial cell-derived iPS (eiPS) arose as colonies, and were isolated and expanded. Reprogrammed cells expressed pluripotency markers SSEA3, SSEA4, TRA 1 60, Oct3/4 and NANOG, and developed into all three germ layers following embryoid body formation. B) Endothelial differentiation: iPS and ES cell lines were aggregated into embryoid bodies in stem cell growth media containing mesoderminducing cytokines. Embryoid bodies were then disaggregated and cultured in endothelial medium supplemented with VEGF. After seven days, a population of CD31+ cells was isolated and further cultured. Mature endothelial cell antigen expression was confirmed by flow cytometry. CD31+ cells were similar to mature endothelial cells in functional assays of proliferation, migration, nitric oxide production and angiogenesis. C) Comparison of fiPS versus eiPS: eiPS differentiated into endothelial cells with greater efficiency than fiPS (21±3% versus 3±2%, P < 0.05). fiPS-derived endothelial cells and eiPS-derived endothelial cells expressed similar levels of endothelial markers CD146, CD31, VEFGR2 and CD34 compared to control endothelial cells. When grown on Matrigel, they formed tubule-like structures with a similar number of vessel connections. In vivo, endothelial cells derived from fiPS and eiPS increased neovasculogenesis in a nude mouse model: vessel density was increased after implantation of endothelial cells from fiPS and eiPS by 3.50 vessel counts (P≤0.001) and 3.47 vessel counts (P≤0.001) respectively, when compared to controls. By comparison control endothelial cells did not increase vessel density compared to control (P > 0.05). Conclusions: Endothelial cells can be isolated from blood and reprogrammed to form pluripotent stem cells with enhanced capacity to differentiate into endothelial cells than those derived from dermal fibroblasts. Endothelial cells derived from both sources promote angiogenesis in vivo, and have major potential for therapeutic applications in vascular regeneration.
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O'Doherty, Michelle. "Endothelial progenitor cells : development of a cell-based therapy." Thesis, Queen's University Belfast, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.602718.
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Much interest currently surrounds the emerging field of regenerative medicine. Cell-based therapies represent a novel therapeutic platform for the treatment of ischaemic diseases, shifting the focus clinically from the management of disease symptoms to their potential cure. Endothelial progenitor cells (EPCs) contribute to vascular repair and angiogenesis. Despite controversy surrounding the heterogeneous nature of these cells in vitro and in vivo, their vasoreparative functions suggest that EPCs have potential clinical value. The aim of this thesis is to further define the precise phenotype, angiogenic properties and potential clinical development of two EPC subtypes and to further elucidate the optimal myeloid angiogenic cell (MAC) or outgrowth endothelial cell (OEC) transplant regimen that is safe and effective prior to large-scale clinical application of these cells for therapeutic angiogenesis. EPCs were isolated from human peripheral blood and cord blood by density gradient centrifugation. Mononuclear cells were cultured on fibronectin or collagen and two different isolation protocols were utilised to obtain MACs and OECs respectively. MACs, previously referred to as early EPCs (eEPCs), were found to be M2 alternatively activated macrophages, which induced angiogenesis via release of IL8 in a paracrine manner both in vitro and in vivo. OECs were also assessed in a similar manner, and the effect of high glucose conditions and senescence on their vasoreparative function was evaluated. The effect of cell density on MAC secretome and vascular contribution was also investigated in vitro, as this represents an important Issue in the clinical and commercial development of a cytotherapy This study has provided a complete analysis of both types of EPCs and shed further light on a number of issues associated with the development of a cell-based treatment strategy for autologous or allogeneic therapy. These findings have imp011ant implications in relation to the harnessing of these cells as a cell therapy for vascular repair of ischaemic tissues.
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Wren, Amanda D. "Pharmacological studies on the actions of endothelins in endothelial repair in vitro." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363301.
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Bethi, Akhila. "Endothelin-1 Induced Phosphorylation of ERK1/2 in Bovine Corneal Endothelial Cells." TopSCHOLAR®, 2012. http://digitalcommons.wku.edu/theses/1191.
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The purpose of this study was to determine whether Endothelin-1 (ET-1) induced cellular responses in bovine corneal endothelial cells (BCECs) involves MAPK pathway by phosphorylating ERK1/2 protein kinase and to find out the phosphorylation patterns of ERK1/2 in confluent and sub-confluent cells. BCECs were isolated from bovine corneas and cultured in medium supplemented with 10% serum. Confluent (contact inhibited) and sub-confluent (actively growing cells) serum starved cells grown in T-75 flasks were treated with 10nM Endothelin-1. The control cells were left untreated. Total cellular protein was isolated using RIPA buffer and quantified according to the Peterson modification of the Lowry method. The level of expression of phosphorylated ERK1/2 (pp44, pp42) proteins relative to overall ERK1/2 (p44, p42) was determined by western blotting technique. Densitometry analysis of immunoblots revealed differential phosphorylation patterns in confluent and sub-confluent cultures. The pERK1/2 levels were significantly increased at 15 min and 24 hrs after post incubation with ET-1, whereas following the initial rise levels declined to 6hrs of incubation with ET-1 in confluent cultures. In sub-confluent cultures pERK1/2 levels increased gradually to 6hrs of incubation with ET-1, returning to pre-incubation levels at 24hrs. In conclusion, ET-1 treatment was shown to induce phosphorylation of ERK1/2 in BCEC. ET-1 treatment in confluent and sub confluent BCEC exhibited time dependent phosphorylation of ERK1/2. ET-1 treatment affected the phosphorylation pattern distinctively in confluent and sub-confluent BCEC. These observations led to the conclusion that ET-1 induced cellular events in BCEC may involve the MAPK cascade and that these ET-1 induced MAPK cascades may exhibit a negative feedback mechanism, suggested by a distinctive oscillations in pERK 1/2 levels. The contrasting effects of ET-1 in confluent and subconfluent cells may suggest a density dependent phosphatase activity.
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Valdimarsdóttir, Gudrun. "TGFβ Signal Transduction in Endothelial Cells". Doctoral thesis, Uppsala University, Ludwig Institute for Cancer Research, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4284.
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<p>Transforming growth factor β (TGFβ) is a multifunctional cytokine that is involved in many biological effects, such as proliferation, migration, differentiation and cell survival. TGFβ regulates cellular responses by binding to a heteromeric complex of type I and type II serine/threonine kinase receptors. The type I receptor, termed activin receptor-like kinase (ALK), acts downstream of the type II receptor and propagates the signal to the nucleus by phosphorylating receptor regulated Smads (R-Smads). The activated R-Smads can associate with the common partner Smad, Smad4, and this complex translocates to the nucleus where it participates in transcriptional regulation of target genes. TGFβ plays an important role in vascular morphogenesis. The aim of this study was to obtain more insight into the mechanisms by which TGFβ can act as an inhibitor or stimulator of angiogenesis Our findings show that in endothelial cells (ECs), TGFβ can activate two distinct type I receptor/Smad signalling pathways with opposite cellular responses. In most cell types, TGFβ signals via the TGFβ type I receptor, ALK5. However, ECs express a predominant endothelial type I receptor, named ALK1. Whereas the TGFβ/ALK1 signalling leads to activation, the TGFβ/ALK5 pathway results in an inhibition of the activation state. This suggests that TGFβ regulates the activation state of the endothelium via a fine balance between these two pathways. We identified genes that are specifically induced by TGFβ mediated ALK1 or ALK5 activation. Id1 was found to be the target gene of the ALK1/Smad1/5 pathway while induction of plasminogen activator inhibitor-1 was activated only by ALK5/Smad2 pathway. Furthermore, ALK1 activated ECs are highly invasive but this property is lost if Id1 expression is specifically knocked-down. ECs invasiveness is highly dependent on αv integrin binding to its extracellular matrix (ECM) protein partner and the invasion requires proteolytic cleavage of the ECM by metalloproteases (MMPs). Hence, TGFβ/ALK1/Id1 pathway may promote invasion by modulating the expression or activity of integrins and MMPs that are well known components of the ECM. Timing and duration of TGFβ signalling are important specificity determinants for its effect on cellular behaviour. After binding to ALK1, TGFβ induces a transient phosphorylation of Smad1/5 but a stable phosphorylation of Smad2 via ALK5. Our studies indicate that Smad7 is potently induced by ALK1 signalling and may recruit a PP1α/TIMAP phosphatase complex to ALK1 to dephosphorylate the receptor and thereby turning off phosphorylation resulting in a temporal activation of TGFβ/ALK1-induced Smad1/5 pathway. This mechanism enables an efficient and tightly temporally controlled activation resulting in the dominance of ALK5 upon prolonged exposure to TGFβ. Bone morphogenetic protein (BMP) is a member of the TGFβ superfamily and signals through Smad1/5. The BMP/Smad1/5 pathway was found to potently activate the endothelium. Id1 was identified as an important BMP target gene in ECs and was sufficient and necessary for BMP-induced EC migration. These studies not only provide new insights into possible molecular mechanisms that underlie activation and quiescence of ECs during physiological angiogenesis but may also explain the vascular phenotypes observed in mice and humans with perturbed TGFβ signalling pathways.</p>
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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.
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Hunter, Nikolas Ross. "In vitro studies on endothelial cells." Thesis, Heriot-Watt University, 1987. http://hdl.handle.net/10399/1040.
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Wood, Peter G. "Intracellular calcium mobilization in endothelial cells." Thesis, University of Newcastle Upon Tyne, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310032.
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Ansari, Abdul-Haq. "Targeting statins to the endothelial cells." Thesis, University of Newcastle Upon Tyne, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438361.
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Cheluvappa, Rajkumar. "Pathophysiology of Liver Sinusoidal Endothelial Cells." Thesis, The University of Sydney, 2008. http://hdl.handle.net/2123/2802.
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Owing to its strategic position in the liver sinusoid, pathologic and morphologic alterations of the Liver Sinusoidal Endothelial Cell (LSEC) have far-reaching repercussions for the whole liver and systemic metabolism. LSECs are perforated with fenestrations, which are pores that facilitate the transfer of lipoproteins and macromolecules between blood and hepatocytes. Loss of LSEC porosity is termed defenestration, which can result from loss of fenestrations and/ or decreases in fenestration diameter. Gram negative bacterial endotoxin (Lipopolysaccharide, LPS) has marked effects on LSEC morphology, including induction LSEC defenestration. Sepsis is associated with hyperlipidemia, and proposed mechanisms include inhibition of tissue lipoprotein lipase and increased triglyceride production by the liver. The LSEC has an increasingly recognized role in hyperlipidemia. Conditions associated with reduced numbers of fenestrations such as ageing and bacterial infections are associated with impaired lipoprotein and chylomicron remnant uptake by the liver and consequent hyperlipidemia. Given the role of the LSEC in liver allograft rejection and hyperlipidemia, changes in the LSEC induced by LPS may have significant clinical implications. In this thesis, the following major hypotheses are explored: 1. The Pseudomonas aeruginosa toxin pyocyanin induces defenestration of the LSEC both in vitro and in vivo 2. The effects of pyocyanin on the LSEC are mediated by oxidative stress 3. Defenestration induced by old age and poloxamer 407 causes intrahepatocytic hypoxia and upregulation of hypoxia-related responses 4. Defenestration of the LSEC seen in old age can be exacerbated by diabetes mellitus and prevented or ameliorated by caloric restriction commencing early in life
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Cheluvappa, Rajkumar. "Pathophysiology of Liver Sinusoidal Endothelial Cells." University of Sydney, 2008. http://hdl.handle.net/2123/2802.
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Doctor of Philosophy(PhD)<br>Owing to its strategic position in the liver sinusoid, pathologic and morphologic alterations of the Liver Sinusoidal Endothelial Cell (LSEC) have far-reaching repercussions for the whole liver and systemic metabolism. LSECs are perforated with fenestrations, which are pores that facilitate the transfer of lipoproteins and macromolecules between blood and hepatocytes. Loss of LSEC porosity is termed defenestration, which can result from loss of fenestrations and/ or decreases in fenestration diameter. Gram negative bacterial endotoxin (Lipopolysaccharide, LPS) has marked effects on LSEC morphology, including induction LSEC defenestration. Sepsis is associated with hyperlipidemia, and proposed mechanisms include inhibition of tissue lipoprotein lipase and increased triglyceride production by the liver. The LSEC has an increasingly recognized role in hyperlipidemia. Conditions associated with reduced numbers of fenestrations such as ageing and bacterial infections are associated with impaired lipoprotein and chylomicron remnant uptake by the liver and consequent hyperlipidemia. Given the role of the LSEC in liver allograft rejection and hyperlipidemia, changes in the LSEC induced by LPS may have significant clinical implications. In this thesis, the following major hypotheses are explored: 1. The Pseudomonas aeruginosa toxin pyocyanin induces defenestration of the LSEC both in vitro and in vivo 2. The effects of pyocyanin on the LSEC are mediated by oxidative stress 3. Defenestration induced by old age and poloxamer 407 causes intrahepatocytic hypoxia and upregulation of hypoxia-related responses 4. Defenestration of the LSEC seen in old age can be exacerbated by diabetes mellitus and prevented or ameliorated by caloric restriction commencing early in life
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Young, Richard Steven. "Calcium entry in tumour endothelial cells." Thesis, University of Leeds, 2014. http://etheses.whiterose.ac.uk/7042/.
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Colorectal cancer liver metastases (CRLM) remain a significant cause of cancer-related mortality. There is an urgent need for novel oncological treatments to support continuing surgical advances. Tumour endothelial cells are emerging as important and unique cells that may be powerful therapeutic targets. Endothelial cell store-operated Ca2+ entry (SOCE) via Ca2+-release activated calcium (CRAC) channels underlies key angiogenic and tumourigenic processes and is the focus of this study. Normal (NEC) and tumour (TEC) endothelial cells were for the first time successfully isolated and characterised from patients with CRLM. Ca2+ entry events were stimulated by agonists, store-depletion and shear stress. TEC express the molecular components of calcium-release activated calcium (CRAC) channels and display SOCE. Novel SOCE inhibitors were developed to potently inhibit SOCE and subsequent angiogenic processes in endothelial cells. A structure-activity drug design strategy allowed key pharmacokinetic and physio-chemical properties to be optimised. Molecular modelling predicted a potential binding site and mechanism of action for SOCE inhibitors. A system for in vivo delivery and plasma measurement of these compounds was established. Drebrin is an actin-binding protein important for cytoskeletal dynamics that has been proposed as a protein target for SOCE inhibitors. Drebrin was significantly up-regulated in CRLM TEC and plays a role in endothelial cell SOCE and cellular migration. However, disruption of the proposed target binding region in drebrin had no influence on pharmacological SOCE inhibition in this study. Novel synthesised SOCE inhibitors have been characterised in vitro, their mechanism of action interrogated and their properties optimised for the next stages of in vivo testing in an animal disease model of CRLM.
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Whyte, Jemima Lois. "Density dependent differentiation of mesenchymal stem cells to endothelial cells." Thesis, University of Manchester, 2010. https://www.research.manchester.ac.uk/portal/en/theses/density-dependent-differentiation-of-mesenchymal-stem-cells-to-endothelial-cells(d839ac9d-3bda-46fb-8e8e-556a85772db9).html.
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The differentiation of mesenchymal stem cells (MSCs) to endothelium is a critical but poorly understood feature of tissue vascularisation and considerable scepticism still remains surrounding this important differentiation event. Defining features of endothelial cells (ECs) are their ability to exist as contact-inhibited polarised monolayers that are stabilised by intercellular junctions, and the expression and activity of endothelial markers. During vasculogenesis, communication between MSCs and differentiated ECs or vascular smooth muscle cells, or between MSCs themselves is likely to influence MSC differentiation. In this study, the possibility that cell density can influence MSC differentiation along the EC lineage was examined. High density plating of human bone marrow-derived MSCs induced prominent endothelial characteristics including cobblestone-like morphology, enhanced endothelial networks, acetylated-low density lipoprotein uptake, vascular growth and stimulated expression of characteristic endothelial markers. Mechanistically, this density-dependent process has been defined. Cell-cell contact-induced Notch signalling was a key initiating step regulating commitment towards an EC lineage, whilst VEGF-A stimulation was required to consolidate the EC fate. Thus, this study not only provides evidence that MSC density is an essential microenvironmental factor stimulating the in vitro differentiation of MSCs to ECs but also demonstrates that MSCs can be differentiated to a functional EC. Taken together, defining how these crucial MSC differentiation events are regulated in vitro, provides an insight into how MSCs differentiate to ECs during postnatal neovascularisation and an opportunity for the therapeutic manipulation of MSCs in vivo, enabling targeted modulation of neovascularisation in ischaemia, wound healing and tumourigenesis.
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Ng, Hoi-man, and 伍凱敏. "Regulation of vascular endothelial growth factor by ginsenoside RG1 inhuman endothelial cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43955915.
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Maillard, Marjorie. "The effects of hyperglycaemia on endothelial barrier function in human endothelial cells." Thesis, University of Nottingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395604.
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Waldman, W. James. "Preservation of natural endothelial cytopathogenicity of cytomegalovirus by propagation in endothelial cells /." The Ohio State University, 1990. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487681788253941.
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Baldoli, E. "MAGNESIUM AND ENDOTHELIAL FUNCTION: COMPARATIVE STUDIES IN MACRO AND MICROVASCULAR ENDOTHELIAL CELLS." Doctoral thesis, Università degli Studi di Milano, 2010. http://hdl.handle.net/2434/150045.
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Mg is referred to as the intracellular divalent cation par excellence. Its biological role is extremely versatile as it can serve structural functions as well as dynamic functions. Accordingly, Mg deficiency has been reported to be involved in the pathogenesis of cardiovascular diseases and, in particular, in atherogenesis.
1)Mg in macrovascular endothelial cells. In cultured macrovascular endothelial cells, low Mg increases tha adhesion of monocytes to the monolayer via upregulation of vascular cell adhesion molecule (VCAM), induces plasminogen activator inhibitor (PAI)1, augments the levels of the pro-inflammatory cytokine interleukin (IL)-1α, impairs endothelial proliferation and promotes cellular senescence (Killilea DW and Ames BN, 2008). Recently, endothelial function has been shown significantly impaired in a model of inherited hypomagnesemia in mice (MgL mice) (Mazur A et al., 2007). All these results point to the fact that low Mg promotes the acquisition of an inflammatory phenotype in endothelium. Since NFkB transcription factors control the inflammatory response and are activated by free radicals, I investigated whether culture in low Mg promotes oxidative stress and activates NFkB in human umbilical vein endothelial cells (HUVEC). Because NFkB activation correlates with marked alterations of the cytokine network, I also studied the secretion profile of inflammatory molecules in cells grown in low Mg. My results highlight molecular events that contribute to the pro-atherogenic effect of Mg deficiency.
2)Mg in microvascular endothelial cells. MEC contribute to inflammation by elaborating cytokines, synthesizing chemical mediators and expressing adhesion molecules which bind leukocytes, thus facilitating their passage in the nearby tissues. In addition, also in the microvasculature the endothelium itself is sensitive to cytokines which profoundly affect its behavior. Low extracellular Mg affects also microvascular endothelial cells. In murine microvascular cells, it has been reported that low Mg induces the synthesis of vascular cell adhesion molecule (VCAM), a marker of inflammation which binds the integrin VLA-4 (very late activation antigen-4) expressed by monocytes and most of the lymphocytes. Focal adhesion of leukocytes to the microvasculature is a key step in inflammation and immune response. In addition, Mg deficiency upregulates IL-1α and IL-6, pleiotropic cytokines implicated in acute phase response and inflammation (Bernardini D. et al, 2005).
Because MEC are important players in inflammation and angiogenesis, I asked whether different concentrations of Mg could affect the behavior of human MEC in vitro. My results demonstrate that culture in low Mg affects human MEC with some differences in respect to HUVEC.
3)TRPM7, a Mg transport channel. The novel Mg transporter TRPM7, a ubiquitously expressed protein with the feature of being both a functional ion channel and kinase, is a critical regulator of Mg homeostasis in vascular cells. Because endothelial cells are very sensitive to extracellular concentrations of Mg, we have investigated the expression and the role of TRPM7 in human macro- and microvascular endothelial cells. I show that the regulation of TRPM7 expression is very different in human MEC vs HUVEC. By siRNA I also demonstrate completely different effects of TRPM7 silencing in HUVEC vs MEC.
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Deshane, Jessy S. "Regulation of HO-1 and its role in angiogenesis." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2009r/deshane.pdf.
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Neilson, Kirstie Jane. "Differentiation of mouse embryonic stem cells into endothelial progenitor cells." Thesis, University of Sheffield, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500200.
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Abdel-Samad, Dima. "Regulation of human endocardial endothelial cells' secretion of endothelin-1 by neuropeptide Y." Thèse, Université de Sherbrooke, 2008. http://savoirs.usherbrooke.ca/handle/11143/4271.
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Endocardial endothelial cells (EECs) can exert a significant influence on cardiac function by releasing various factors such as nitric oxide (NO), prostanoids, endothelin-1 (ET-1) and angiotensin II (Ang II). Recently, results obtained in our laboratory demonstrated the presence of NPY and its receptors, Y[subscript 1] and Y[subscript 2], as well as ET-1 and its receptors, ET[subscript A] and ET[subscript B], at the level of endocardial endothelial cells (EECs). We have also shown that NPY induces a sustained rise in the intracellular calcium level of these cells, and that only right ventricular EECs have the capacity of secreting NPY. Moreover, the evidence in the literature has become plentiful about complex interactions existing between ET-1 and other cardioactive mediators, such as NO and Ang II. Based on the above-mentioned data, the objective of this study was to investigate if a dialogue equally exists between the systems of NPY and ET-1 at the level of human right (hREECs) and left (hLEECs) ventricular EECs. Using the technique of indirect immunofluorescence coupled to 3-D confocal microscopy, as well as ELISA, our results show that increasing concentrations of NPY (10[superscript -15], 10[superscript -10] and 10[superscript -5]M) induce the release of ET-1 from REECs and LEECs in a time- and dose-dependent fashion. However, right ventricular EECs seem to have a higher ET-1 secretory capacity as compared to their left counterparts. Upon the use of selective antagonists for the NPY receptors, Y[subscript 1], Y[subscript 2] and Y[subscript 5], and the ET-1 receptors, ET[subscript A] and ET[subscript B], our results demonstrated that in REECs the NPY-induced release of ET-1 seems to be primarily due to Y[subscript 2] receptor activation, with the subsequent activation of the ET[subscript A] and ET[subscript B] receptors by the released ET-1. On the other hand, in LEECs, the NPY-evoked secretion of ET-1 seems to be mainly the result of Y[subscript 5] receptor activation by NPY. Unlike REECs, the ET-1 released by NPY in this type of cells does not seem to be contributing further to its own release by activation of its ET[subscript A] and ET[subscript B] receptors. Therefore, our results suggest that NPY is a regulator of ET-I secretion at the level of human EECs, and that this secretory process of ET-1 is different between the right and left ventricular cells. Moreover, these results serve to highlight and endorse the important sensory and tuning roles that right and left ventricular EECs possess, respectively. The ability of EECs to contribute to the local as well as systemic release of factors, such as NPY and ET-1, can affect not only the excitation-secretion coupling of EECs and the excitation-contraction coupling of cardiomyocytes, but also the physiological and pathophysiological state of the underlying, heart muscle.
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Shaikh, Mohsin Ahmed. "Models of coupled smooth muscleand endothelial cells." Thesis, University of Canterbury. Centre for Bioengineering, 2011. http://hdl.handle.net/10092/6190.
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Impaired mass transfer characteristics of blood borne vasoactive species such
as ATP in regions such as an arterial bifurcation have been hypothesized as a
prospective mechanism in the aetiology of atherosclerotic lesions. Arterial endothelial
(EC) and smooth muscle cells (SMC) respond differentially to altered
local hemodynamics and produce coordinated macro-scale responses via intercellular
communication. Using a computationally designed arterial segment comprising
large populations of mathematically modelled coupled ECs & SMCs, we
investigate their response to spatial gradients of blood borne agonist concentrations
and the effect of micro-scale driven perturbation on the macro-scale. Altering
homocellular (between same cell type) and heterocellular (between different
cell types) intercellular coupling we simulated four cases of normal and pathological
arterial segments experiencing an identical gradient in the concentration of
the agonist. Results show that the heterocellular calcium (Ca2+) coupling between
ECs and SMCs is important in eliciting a rapid response when the vessel segment
is stimulated by the agonist gradient. In the absence of heterocellular coupling,
homocellular Ca2+ coupling between smooth muscle cells is necessary for propagation
of Ca2+ waves from downstream to upstream cells axially. Desynchronized
intracellular Ca2+ oscillations in coupled smooth muscle cells are mandatory for
this propagation. Upon decoupling the heterocellular membrane potential, the
arterial segment looses the inhibitory effect of endothelial cells on the Ca2+ dynamics
of underlying smooth muscle cells. The full system comprising hundreds
of thousands of coupled nonlinear ordinary differential equations simulated on the
massively parallel Blue Gene architecture. The use of massively parallel computational
architectures shows the capability of this approach to address macro-scale
phenomena driven by elementary micro-scale components of the system.
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Goyal, Pankaj. "Dual function of LIMK2 in endothelial cells." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-41291.
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Kemp, Sarah J. G. "Focal adhesion kinase signalling in endothelial cells." Thesis, University of Leicester, 2002. http://hdl.handle.net/2381/29413.
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The angiogenic factor vascular endothelial growth factor (VEGF) induces migration and cytoskeletal changes in endothelial cells. The mechanism by which VEGF signals was not known but it was possible an adhesion associated protein such as focal adhesion kinase (FAK) was involved. Further investigation revealed VEGF caused a marked activation of tyrosine phosphorylation of FAK in HUVE cells, which was time and concentration dependent. The PI3K inhibitor wortmannin partially inhibited VEGF stimulated FAK phosphorylation and it inhibited phosphorylation in response to lysophosphatidic acid and VEGF induced membrane ruffling. The tyrosine kinases Src and Fyn were associated with FAK upon VEGF stimulation of HUVE cells. VEGF stimulated recruitment to FAK would allow Src family kinases to stimulate tyrosine phosphorylation of FAK thereby mediating the effects of VEGF on FAK tyrosine phosphorylation. Analysis of a functional consequence of VEGF stimulated FAK tyrosine phosphorylation was assessed by displacement of endogenous FAK by microinjection of a truncated C-terminal FAK. A reduction in the distance migrated by VEGF stimulated endothelial cells was demonstrated, indicating VEGF signals via FAK to induce migration. To investigate the role of FAK in other endothelial cell functions, epitope tagged FAK mutants were generated and characterised. Co-expression of the FAK mutants and in addition, a Fyn kinase inactive protein, gave some insight into the mechanism of FAK tyrosine phosphorylation. Expression of the mutant FAK proteins revealed neither the autophosphorylation site or the kinase ability of FAK are required to provide survival signals from FAK in adherent endothelial cells however the truncated C-terminal FAK did induce apoptosis.
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Chan, Giulia. "Regulation of viability in corneal endothelial cells." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1444592/.
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The major cause of corneal opacity and resultant visual loss is a critical decrease in corneal endothelial cell density. Due to the fact that corneal endothelial cells do not generally proliferate, cell densities gradually decrease in the corneal endothelium with age. Before we can begin to aid patients with decreasing endothelial cell densities, by inhibiting cell death or stimulating cell proliferation, it is necessary to understand the basic cell signalling that underlies these processes. As human tissue is difficult to obtain, a representative animal model of corneal endothelium was devised. Analysis of cell morphology and expression of ct1 type VIII collagen were used to verify that primary cells derived from an explant model of mouse corneal cells were endothelial. A range of phenotypic and functional cellular features were also analysed to assess the usefulness of primary mouse corneal endothelial cultures as a model for human corneal endothelium. These included tight junction protein localization, proliferative responses to growth factor stimulation and ERK1/2 activation following growth factor stimulation. From these analyses, it was shown that primary mouse corneal endothelial cultures provide a representative model of the human corneal endothelium. A similar comparison was also made between primary mouse corneal endothelial cultures and an SV40 transformed mouse corneal endothelial cell line. Studies revealed significant differences in propensity to proliferate, junctional integrity, ERK1/2 activation, expression of apoptotic proteins and sensitivity to staurosporine-induced apoptosis between primary cells and the SV40 transformed cell line, suggesting that the SV40 transformed cell line is a less appropriate model for primary mouse corneal endothelial cells. In conclusion, the derivation and characterisation of mouse primary corneal endothelial cells provides a better model of the corneal endothelium, that offers greater understanding of cellular responses and which may eventually lead to the development of alternative therapies for primary corneal endotheliopathies.
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Jalilian, E. "Characterization of progenitors of endothelial cells (PECs)." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1560479/.
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There are a number of different stem cell sources that have the potential to be used as therapeutics in vascular degenerative diseases such as diabetic retinopathy. On the one hand, there are so called endothelial progenitor cells (EPCs), which are typically derived from adult blood. They carry the marker CD34, but the true nature and definition of EPCs is still controversial. On the other hand, there are embryonic precursors of endothelial cells (PECs), which also express CD34, and which can be differentiated from embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) in vitro. Furthermore, a subpopulation of human umbilical cord endothelial cells (HUVECs) has also been shown to express CD34. In this study, It was aimed to compare these three different CD34 positive cell populations by full genome transcriptional profiling (RNAseq). To this end I firstly optimised a PEC differentiation protocol and found that VEGF is critical for the transition from mesodermal precursors to PECs. Secondly, I found signalling pathways that regulate CD34 expression in HUVECs and showed a close correlation between CD34 expression and the endothelial tip/stalk cell phenotypes. Thirdly, principal component analysis (PCA) of RNAseq data showed that blood-derived EPCs are fundamentally different from iPS-derived PECs. Lastly, I also identified from RNAseq data number of potentially novel PEC markers. Once validated such novel markers of PECs and EPCs will be useful to better define these cell populations, facilitating the translation of regenerative approaches in this field as well as providing potentially novel diagnostic tools.
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Franses, Joseph W. (Joseph Wang). "Regulatory roles of endothelial cells in cancer." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/65518.
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Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, June 2011.<br>"May 2011." Cataloged from PDF version of thesis.<br>Includes bibliographical references (p. 109-121).<br>This thesis describes the biochemical regulatory impact of endothelial cells, the cells that line all blood vessels, in cancer. Our work draws from concepts in vascular repair and tissue engineering and extends the view of tumor vessels from perfusing tubes to delivery platforms lined with potent paracrine regulatory cells. We focus on how the endothelial cells themselves regulate tumor biology in a state-dependent fashion. We found that healthy endothelial cells inhibit cancer cell proliferation, invasiveness, and inflammatory signaling and that a defined perturbation of the healthy endothelial cell state - silencing of the gene encoding perlecan - causes loss of the invasion-inhibitory capabilities of endothelial cells by transcriptional upregulation of IL-6. The use of matrixembedded endothelial implants enabled the effects in cell culture to be expanded and validated in animal models. Moreover, endothelial cells exposed to a pathologically activating and inflammatory culture environment, similar to endothelial cells exposed to the atherosclerotic milieu, were leaky and inflamed, with dysregulated proliferative and leukocyte binding properties. Unlike healthy endothelial cells, which suppress cancer cell proliferation and metastasis, these dysfunctional endothelial cells instead aggressively stimulated cancer cell inflammatory signaling and invasiveness, which correlated with stimulation of spontaneous metastasis when implanted as matrixembedded cell implants adjacent to tumors. Fascinatingly we were able to identify markers of endothelial dysfunction, including reduction of endothelial perlecan expression, in human non-small cell lung carcinoma specimens. The state-dependent impact of endothelial cells on cancer biology adds another element to stromal regulation of cancer and brings together a range of disciplines and disparate findings regarding vascular control of tumors. That healthy endothelial cells suppress and dysfunctional cells promote tumor aggression may help to explain undesired effects of therapies that target tumor blood vessels. The harnessing of tissue engineering to regulate vascular and cancer biology may motivate the development of innovative pharmacologic and cell-based therapies for cancer.<br>by Joseph W. Franses.<br>Ph.D.
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May, Michael Jonathan. "Cytokine-induced signal transduction in endothelial cells." Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339150.
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Prasad, Raju. "Endothelial progenitor cells, vascular function, and exercise." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 59 p, 2009. http://proquest.umi.com/pqdweb?did=1654501181&sid=4&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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Mancardi, Sabrina. "Characterization of endothelial cells of lymphatic vessels." Thesis, Open University, 2001. http://oro.open.ac.uk/54568/.
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Endothelial cells form the inner lining of blood and lymphatic vessels. In mice only tumours of the blood vessel endothelium (haemangiomas) have been thus far reported. In the first part of this thesis is described a highly reproducible method for the induction of benign tumours of the lymphatic endothelial cells (lymphangioma) in mice, by intraperitoneal injection of incomplete Freund's adjuvant. Different criteria have been used in order to establish the nature of the induced lesion. Morphological and histophatological studies of the tumour developed in the peritoneal cavity revealed the presence of cells at various levels of vascular development. Expression of the endothelial markers PECAM/CD31, ICAM-l/CD54, ICAM 2/CDI02 as well as the vascular endothelial growth factor (VEGF) receptor Flk-I, the endothelial cell specific receptors Tie-I, Tie-2, and the lymphatic endothelial specific Flt-4 was identified. When the lesion was induced in ~- galactosidase knock-in Flt-4 +/- mice, the tumour endothelia could be stained blue in a number of tumour cells. Tumour-derived cells were propagated in vitro where they spontaneously differentiated, forming vessel-like structures. This evidence leads to the conclusion that this is the first experimental protocol for the induction of a lymphatic endothelium hyperplasia in mice peritoneum. The second part of this thesis describes the use of this model system to investigate the profile of chemokine expression in murine lymphangiomas and in lymphangioma-derived lymphatic endothelial primary cultures. Chemokines are a superfamily of small, secreted chemoattractant molecules that plays a key role in the immune cell trafficking. Although production of chemokines by vascular endothelial cells has been extensively documented, there is much less information regarding the lymphatic endothelium. The reported results are the first detailed analysis of chemokine production by lymphatic endothelial cells. Chemokines belonging to all three subfamilies (CXC, CC and C), were found to be expressed in lymphangioma. Among these molecules is remarkable the identification of CIO, a molecule previously identified only in the bone marrow. The molecular as well as functional assays performed provide an indication of the signals that mediate the recruitment of leukocytes into lymphatic vessels.
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Kim, Sung Kyu. "Endothelial cell interaction with collagen." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709002.
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Platt, Manu Omar. "Role of Shear Stress in the Differential Regulation of Endothelial Cathepsins and Cystatin C." Diss., Georgia Institute of Technology, 2006. http://hdl.handle.net/1853/11635.
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The importance of shear stress in vascular biology and pathophysiology has been highlighted by the focal development patterns of atherosclerosis, abdominal aortic aneurysms, and heart valve disease in regions exposed to disturbed flow leading to low or oscillatory shear stress at the wall of the blood vessel or the surface of the valve leaflet. The novel and significant finding of this study is that mouse aortic endothelial cell exposure to pro-atherogenic oscillatory shear stress (OS) (+/- 5 dynes/cm2) increased their production of cathepsins, the family of lysosomal cysteine proteases that are potent elastases and collagenases leading to protease degradation and remodeling of the extracellular matrix structural components. Conversely, atheroprotective unidirectional laminar shear stress (LS) (15 dynes/cm2) decreased elastase and gelatinase activities of endothelial cells through a shear stress mediated reduction in cathepsins K, L, and S activity. Their endogenous inhibitor, cystatin C, was found to be inversely regulated by shear stress; LS increased its secretion by endothelial cells while OS decreased it. Binding of free cystatin C in the conditioned media to carboxymethylated papain coated agarose beads led to an increase in cathepsin activity since the available cathepsin was not inhibited. To verify these findings in human samples, immunohistochemical analysis of cystatin C and cathepsin K was performed on human coronary arteries. Cathepsin K stained strongly in the endothelial layer of vessels with degraded internal elastic lamina while cystatin C staining intensity was strongest overlying minimally diseased vessels. Additional roles for cathepsins K, L, and S were found in endothelial cell alignment in response to unidirectional laminar shear stress, endothelial cell migration, and programmed cell death. We conclude that there is an inverse regulation of cathepsins and cystatin C in endothelial cells by LS and OS and identify the cathepsin family of proteases as potential targets for therapeutic intervention of cardiovascular disease development at sites of disturbed flow.
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Kono, Tomoya. "Differentiation of lymphatic endothelial cells from embryonic stem cells on OP9 stromal cells." Kyoto University, 2008. http://hdl.handle.net/2433/135863.
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Johansson, Magnus. "Role of Islet Endothelial Cells in β-cell Function and Growth". Doctoral thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6801.
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The pancreatic islets are collections of endocrine cells, dispersed throughout the pancreas. In adult islets, endocrine cells are closely associated with capillary endothelial cells and receive a high blood perfusion. Transplanted pancreatic islets, on the other hand, have a vascular disturbance, manifested as decreased blood vessel density. Besides impaired islet blood perfusion and oxygenation, this means that the normal close proximity between endothelial cells and β-cell in adult islets is interrupted. The aim of the thesis was to investigate if, and to what extent, β-cells and islet endothelial cells can interact with one another. This hypothesis was investigated during physiological growth of pancreatic islets, following transplantation and in vitro. We observed that islet endothelial and endocrine cell replication coincided immediately after birth, as well as during pregnancy. In pregnant animals, β-cell proliferation colocalized to islets with increased endothelial cell replication, indicating that the two processes were interconnected. The pregnancy hormone prolactin favored endothelial cell replication, and these activated cells could then augment β-cell proliferation. We found that prolactin pretreatment increased blood vessel density and oxygen tension in islets after transplantation. Furthermore, prolactin pretreatment improved endocrine function in a minimal islet transplant model. Partial pancreatectomy performed in association with islet transplantation improved revascularization, oxygen tension and glucose stimulated insulin release from the graft. In conclusion, the findings suggest that endocrine and endothelial cells interact with one another to regulate growth and function in pancreatic islets. This may form the basis for interventions aiming to improve revascularization and function of transplanted islets.