Showing papers on "Vascular endothelial growth factor B published in 2003"
TL;DR: It is shown here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts.
Abstract: Vascular endothelial growth factor (VEGF-A) is a major regulator of blood vessel formation and function. It controls several processes in endothelial cells, such as proliferation, survival, and migration, but it is not known how these are coordinately regulated to result in more complex morphogenetic events, such as tubular sprouting, fusion, and network formation. We show here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts. The tip cells respond to VEGF-A only by guided migration; the proliferative response to VEGF-A occurs in the sprout stalks. These two cellular responses are both mediated by agonistic activity of VEGF-A on VEGF receptor 2. Whereas tip cell migration depends on a gradient of VEGF-A, proliferation is regulated by its concentration. Thus, vessel patterning during retinal angiogenesis depends on the balance between two different qualities of the extracellular VEGF-A distribution, which regulate distinct cellular responses in defined populations of endothelial cells.
2,737 citations
TL;DR: The data suggest that IL-8 directly enhanced endothelial cell proliferation, survival, and MMP expression in CX CR1- and CXCR2-expressing endothelial cells and regulated angiogenesis.
Abstract: IL-8, a member of the chemokine family, has been shown to play an important role in tumor growth, angiogenesis, and metastasis. The objective of this study was to determine the mechanism of IL-8-mediated angiogenesis. We examined the direct role of IL-8 in angiogenesis by examining IL-8 receptor expression on endothelial cells and their proliferation, survival, and matrix metalloproteinases (MMPs) production. We demonstrate that HUVEC and human dermal microvascular endothelial cells constitutively express CXCR1 and CXCR2 mRNA and protein. Recombinant human IL-8 induced endothelial cell proliferation and capillary tube organization while neutralization of IL-8 by anti-IL-8 Ab blocks IL-8-mediated capillary tube organization. Incubation of endothelial cells with IL-8 inhibited endothelial cell apoptosis and enhanced antiapoptotic gene expression. Endothelial cells incubated with IL-8 had higher levels of Bcl-x L :Bcl-x S and Bcl-2:Bax ratios. Furthermore, incubation of endothelial cells with IL-8 up-regulated MMP-2 and MMP-9 production and mRNA expression. Our data suggest that IL-8 directly enhanced endothelial cell proliferation, survival, and MMP expression in CXCR1- and CXCR2-expressing endothelial cells and regulated angiogenesis.
1,210 citations
TL;DR: Recent findings that VEGFs secreted by epithelia, including the retinal pigment epithelium (RPE), are likely to mediate paracrine vascular survival signals for adjacent endothelia may explain the pathogenesis of subretinal neovascularisation in AMD.
884 citations
TL;DR: A novel role for IL-17 is revealed as a CD4 T-cell-derived mediator of angiogenesis that stimulates vascular endothelial cell migration and cord formation and regulates production of a variety of proangiogenic factors.
804 citations
TL;DR: The most important endothelial functions will be described, their role in blood vessel formation, in coagulation and fibribolysis, in the regulation of vascular tone as well as their participation in inflammatory reactions and in tumor neoangiogenesis.
Abstract: Endothelial cells play a wide variety of critical roles in the control of vascular function. Indeed, since the early 1980s, the accumulating knowledge of the endothelial cell structure as well as of the functional properties of the endothelial cells shifted their role from a passive membrane or barrier to a complex tissue with complex functions adaptable to needs specific in time and location. Hence, it participates to all aspects of the vascular homeostasis but also to physiological or pathological processes like thrombosis, inflammation, or vascular wall remodeling. Some of the most important endothelial functions will be described in the following review and more specifically, their role in blood vessel formation, in coagulation and fibribolysis, in the regulation of vascular tone as well as their participation in inflammatory reactions and in tumor neoangiogenesis.
684 citations
TL;DR: Selective activation of VEGF receptor–1 stimulated hepatocyte but not endothelial proliferation in vivo and reduced liver damage in mice exposed to a hepatotoxin, suggesting VEGFR-1 agonists may have therapeutic potential for preservation of organ function in certain liver disorders.
Abstract: The vascular endothelium was once thought to function primarily in nutrient and oxygen delivery, but recent evidence suggests that it may play a broader role in tissue homeostasis. To explore the role of sinusoidal endothelial cells (LSECs) in the adult liver, we studied the effects of vascular endothelial growth factor (VEGF) receptor activation on mouse hepatocyte growth. Delivery of VEGF-A increased liver mass in mice but did not stimulate growth of hepatocytes in vitro, unless LSECs were also present in the culture. Hepatocyte growth factor (HGF) was identified as one of the LSEC-derived paracrine mediators promoting hepatocyte growth. Selective activation of VEGF receptor-1 (VEGFR-1) stimulated hepatocyte but not endothelial proliferation in vivo and reduced liver damage in mice exposed to a hepatotoxin. Thus, VEGFR-1 agonists may have therapeutic potential for preservation of organ function in certain liver disorders.
643 citations
TL;DR: Angiogenesis, in response to tissue injury, is a dynamic process that is highly regulated by signals from both serum and the surrounding extracellular matrix (ECM) environment, which regulates angiogenesis by providing scaffold support and signaling roles.
Abstract: Angiogenesis is critical to wound repair. Newly formed blood vessels participate in provisional granulation tissue formation and provide nutrition and oxygen to growing tissues. In addition, inflammatory cells require the interaction with and transmigration through the endothelial basement membrane to enter the site of injury. Angiogenesis, in response to tissue injury, is a dynamic process that is highly regulated by signals from both serum and the surrounding extracellular matrix (ECM) environment. Vascular endothelial growth factor, angiopoietin, fibroblast growth factor, and transforming growth factor beta are among those most potent angiogenic cytokines in wound angiogenesis. The cooperative regulation of them is essential for wound repair. Migration of endothelial cells and development of new capillary vessels during wound repair is dependent on not only the cells and cytokines present but also the production and organization of ECM components both in granulation tissue and in endothelial basement membrane. The ECM regulates angiogenesis by providing scaffold support and signaling roles. They also serve as a reservoir and modulator for growth factors. Laminins are the major noncollagenous ECM of endothelial basement membrane. Two newly recognized laminins, 8 and 10, are the major laminins produced by human dermal microvascular endothelial cells. Laminin 10 is highly expressed in blood vessels around skin wounds. Laminin 8 promotes dermal endothelial cell attachment, migration, and tubule formation. Integrins with either beta 1 or alpha v subunits are the major cellular surface receptors for ECM molecules and mediate the interactions between cells and ECM during wound angiogenesis.
637 citations
TL;DR: In relation specifically to the endocardial endothelium, an active transendothelial physicochemical gradient for various ions, or blood-heart barrier, has been demonstrated, and linkage of this blood- heart barrier to the various other endothelia-mediated signaling pathways or to the putative vascular endothelialium-derived hyperpolarizing factors remains to be determined.
Abstract: Experimental work during the past 15 years has demonstrated that endothelial cells in the heart play an obligatory role in regulating and maintaining cardiac function, in particular, at the endocardium and in the myocardial capillaries where endothelial cells directly interact with adjacent cardiomyocytes. The emerging field of targeted gene manipulation has led to the contention that cardiac endothelial-cardiomyocytal interaction is a prerequisite for normal cardiac development and growth. Some of the molecular mechanisms and cellular signals governing this interaction, such as neuregulin, vascular endothelial growth factor, and angiopoietin, continue to maintain phenotype and survival of cardiomyocytes in the adult heart. Cardiac endothelial cells, like vascular endothelial cells, also express and release a variety of auto- and paracrine agents, such as nitric oxide, endothelin, prostaglandin I(2), and angiotensin II, which directly influence cardiac metabolism, growth, contractile performance, and rhythmicity of the adult heart. The synthesis, secretion, and, most importantly, the activities of these endothelium-derived substances in the heart are closely linked, interrelated, and interactive. It may therefore be simplistic to try and define their properties independently from one another. Moreover, in relation specifically to the endocardial endothelium, an active transendothelial physicochemical gradient for various ions, or blood-heart barrier, has been demonstrated. Linkage of this blood-heart barrier to the various other endothelium-mediated signaling pathways or to the putative vascular endothelium-derived hyperpolarizing factors remains to be determined. At the early stages of cardiac failure, all major cardiovascular risk factors may cause cardiac endothelial activation as an adaptive response often followed by cardiac endothelial dysfunction. Because of the interdependency of all endothelial signaling pathways, activation or disturbance of any will necessarily affect the others leading to a disturbance of their normal balance, leading to further progression of cardiac failure.
626 citations
TL;DR: Given the central role of the endothelium in the development and clinical course of Atherosclerosis, endothelial function testing may serve as a useful biomarker of atherosclerosis.
Abstract: The endothelium is the monolayer of endothelial cells lining the lumen of all blood vessels. These cells function as a protective biocompatible barrier between all tissues and the circulating blood. Endothelial cells also function as a selective sieve to facilitate bidirectional passage of macromolecules and blood gases to and from tissues and blood. The strategic location of the endothelium allows it to “sense” changes in hemodynamic forces and blood-borne signals and “respond” by releasing a number of autocrine and paracrine substances. A balanced release of these bioactive factors facilitates vascular homeostasis. Endothelial cell dysfunction disrupts this balance, thereby predisposing the vessel wall to vasoconstriction, leukocyte adherence, platelet activation, mitogenesis, pro-oxidation, thrombosis, impaired coagulation, vascular inflammation, and atherosclerosis.1 Our understanding of these endothelial cell responses has led to the development of tests that are believed to reflect endothelial cell dysfunction or integrity in vivo. Given the central role of the endothelium in the development and clinical course of atherosclerosis, endothelial function testing may serve as a useful biomarker of atherosclerosis.
Nitric oxide (NO) is the key endothelium-derived relaxing factor that plays a pivotal role in the maintenance of vascular tone and reactivity.2 In addition to being the main determinant of basal vascular smooth muscle tone, NO acts to negate the actions of potent endothelium-derived contracting factors such as angiotensin II and endothelin-1. In addition, NO serves to inhibit platelet and white cell activation and to maintain the vascular smooth muscle in a nonproliferative state. NO is synthesized from l-arginine under the influence of the enzyme NO synthase (NOS). NOS requires a critical cofactor, tetrahydrobiopterin, to facilitate NO production. Tetrahydrobiopterin deficiency leads to an “uncoupling” of NOS that results in the formation of untoward oxidants such as superoxide and hydrogen peroxide (versus NO) with resultant impairment in endothelial function. …
575 citations
TL;DR: During angiogenesis endothelial SEMA3 proteins endow the vascular system with the plasticity required for its reshaping by controlling integrin function.
Abstract: The motility and morphogenesis of endothelial cells is controlled by spatio-temporally regulated activation of integrin adhesion receptors, and integrin activation is stimulated by major determinants of vascular remodelling. In order for endothelial cells to be responsive to changes in activator gradients, the adhesiveness of these cells to the extracellular matrix must be dynamic, and negative regulators of integrins could be required. Here we show that during vascular development and experimental angiogenesis, endothelial cells generate autocrine chemorepulsive signals of class 3 semaphorins (SEMA3 proteins) that localize at nascent adhesive sites in spreading endothelial cells. Disrupting endogenous SEMA3 function in endothelial cells stimulates integrin-mediated adhesion and migration to extracellular matrices, whereas exogenous SEMA3 proteins antagonize integrin activation. Misexpression of dominant negative SEMA3 receptors in chick embryo endothelial cells locks integrins in an active conformation, and severely impairs vascular remodelling. Sema3a null mice show vascular defects as well. Thus during angiogenesis endothelial SEMA3 proteins endow the vascular system with the plasticity required for its reshaping by controlling integrin function.
552 citations
TL;DR: It is demonstrated that anti-VEGF antibodies and sFlt-1 cause rapid glomerular endothelial cell detachment and hypertrophy, in association with down-regulation of nephrin, a key epithelial protein in the glomersular filtration apparatus, suggesting that down- regulation or neutralization of circulating VEGF may play an important role in the induction of proteinuria in various kidney diseases, some forms of cancer therapy and also in women with preeclampsia.
TL;DR: It is shown here that vascular endothelial growth factor but not basic fibroblast growth factor can induce gene expression of Notch1 and its ligand, Delta-like 4 (Dll4), in human arterial endothelial cells.
Abstract: Notch and its ligands play critical roles in cell fate determination. Expression of Notch and ligand in vascular endothelium and defects in vascular phenotypes of targeted mutants in the Notch pathway have suggested a critical role for Notch signaling in vasculogenesis and angiogenesis. However, the angiogenic signaling that controls Notch and ligand gene expression is unknown. We show here that vascular endothelial growth factor (VEGF) but not basic fibroblast growth factor can induce gene expression of Notch1 and its ligand, Delta-like 4 (Dll4), in human arterial endothelial cells. The VEGF-induced specific signaling is mediated through VEGF receptors 1 and 2 and is transmitted via the phosphatidylinositol 3-kinase/Akt pathway but is independent of mitogen-activated protein kinase and Src tyrosine kinase. Constitutive activation of Notch signaling stabilizes network formation of endothelial cells on Matrigel and enhances formation of vessel-like structures in a three-dimensional angiogenesis model, whereas blocking Notch signaling can partially inhibit network formation. This study provides the first evidence for regulation of Notch/Delta gene expression by an angiogenic growth factor and insight into the critical role of Notch signaling in arteriogenesis and angiogenesis.
TL;DR: It is demonstrated that some lineage-specific genes are only expressed during distinct developmental stages and new molecular markers for blood vascular and lymphatic endothelium are identified with important implications for future studies of vascular development and function.
Abstract: In mammals, the lymphatic vascular system develops by budding of lymphatic progenitor endothelial cells from embryonic veins to form a distinct network of draining vessels with important functions in the immune response and in cancer metastasis. However, the lineage-specific molecular characteristics of blood vascular versus lymphatic endothelium have remained poorly defined. We isolated lymphatic endothelial cells (LECs) and blood vascular endothelial cells (BVECs) by immunomagnetic isolation directly from human skin. Cultured LECs but not BVECs expressed the lymphatic markers Prox1 and LYVE-1 and formed LYVE-1-positive vascular tubes after implantation in vivo. Transcriptional profiling studies revealed increased expression of several extracellular matrix and adhesion molecules in BVECs, including versican, collagens, laminin, and N-cadherin, and of the growth factor receptors endoglin and vascular endothelial growth factor receptor-1/Flt-1. Differential immunostains of human skin confirmed the blood vessel-specific expression of these genes. During embryonic development, endoglin expression was gradually down-regulated on lymphatic endothelium whereas vascular endothelial growth factor receptor-1 was absent from lymphatics. We also identified several genes with specific expression in LECs. These results demonstrate that some lineage-specific genes are only expressed during distinct developmental stages and they identify new molecular markers for blood vascular and lymphatic endothelium with important implications for future studies of vascular development and function.
TL;DR: This study compares, for the first time, angiogenesis and lymphangiogenesis induced by gene transfer of different human VEGFs, and shows that VEGF-D is the most potent member when delivered via an adenoviral vector into skeletal muscle.
Abstract: Optimal angiogenic and lymphangiogenic gene therapy requires knowledge of the best growth factors for each purpose. We studied the therapeutic potential of human vascular endothelial growth factor (VEGF) family members VEGF-A, VEGF-B, VEGF-C, and VEGF-D as well as a VEGFR-3–specific mutant (VEGF-C 156S ) using adenoviral gene transfer in rabbit hindlimb skeletal muscle. The significance of proteolytic processing of VEGF-D was explored using adenoviruses encoding either full-length or mature (ΔNΔC) VEGF-D. Adenoviruses expressing potent VEGFR-2 ligands, VEGF-A and VEGF-D ΔNΔC , induced the strongest angiogenesis and vascular permeability effects as assessed by capillary vessel and perfusion measurements, modified Miles assay, and MRI. The most significant feature of angiogenesis induced by both VEGF-A and VEGF-D ΔNΔC was a remarkable enlargement of microvessels with efficient recruitment of pericytes suggesting formation of arterioles or venules. VEGF-A also moderately increased capillary density and created glomeruloid bodies, clusters of tortuous vessels, whereas VEGF-D ΔNΔC –induced angiogenesis was more diffuse. Vascular smooth muscle cell proliferation occurred in regions with increased plasma protein extravasation, indicating that arteriogenesis may be promoted by VEGF-A and VEGF-D ΔNΔC . Full-length VEGF-C and VEGF-D induced predominantly and the selective VEGFR-3 ligand VEGF-C 156S exclusively lymphangiogenesis. Unlike angiogenesis, lymphangiogenesis was not dependent on nitric oxide. The VEGFR-1 ligand VEGF-B did not promote either angiogenesis or lymphangiogenesis. Finally, we found a positive correlation between capillary size and vascular permeability. This study compares, for the first time, angiogenesis and lymphangiogenesis induced by gene transfer of different human VEGFs, and shows that VEGF-D is the most potent member when delivered via an adenoviral vector into skeletal muscle.
TL;DR: The evidence that transport of L-arginine and glucose in endothelial and smooth muscle cells is modulated by bacterial endotoxin, proinflammatory cytokines, and atherogenic lipids is critically reviewed.
Abstract: While transport processes for amino acids and glucose have long been known to be expressed in the luminal and abluminal membranes of the endothelium comprising the blood-brain and blood-retinal bar...
TL;DR: The findings suggest that FTY720 or its analogs may find utility in the therapeutic regulation of vascular permeability, an important process in angiogenesis, inflammation, and pathological conditions such as sepsis, hypoxia, and solid tumor growth.
TL;DR: Tissue hypoxia/ischemia plays an important role in determining the progression of ischemic heart disease and cancer and novel therapeutic approaches that involve stimulating angiogenesis in isChemic tissue and inhibiting angiogenic in neoplastic tissue are currently being evaluated in clinical trials.
Abstract: Vascular development involves vasculogenesis, in which endothelial cells form a primary tubular network, as well as angiogenesis, in which vessel size and structure are modified based upon flow and branching occurs to insure that all cells receive adequate O2 delivery. In adults, angiogenesis occurs in response to tissue hypoxia/ischemia and plays an important role in determining the progression of ischemic heart disease and cancer. A critical molecular pathway induced by hypoxia/ischemia is the activation of hypoxia-inducible factor 1, a transcriptional activator of genes encoding vascular endothelial growth factor and other important mediators of angiogenesis. Novel therapeutic approaches that involve stimulating angiogenesis in ischemic tissue and inhibiting angiogenesis in neoplastic tissue are currently being evaluated in clinical trials.
TL;DR: This study demonstrates the applicability of custom-focused microarray technology in addressing hypothesis-driven questions regarding the action of antidepressants by examining the expression of other neurotrophic-growth factors and related signaling pathways in the hippocampus in response to ECS using a custom growth factor microarray chip.
Abstract: Electroconvulsive seizure therapy (ECS) is a clinically proven treatment for depression and is often effective even in patients resistant to chemical antidepressants However, the molecular mechanisms underlying the therapeutic efficacy of ECS are not fully understood One theory that has gained attention is that ECS and other antidepressants increase the expression of select neurotrophic factors that could reverse or block the atrophy and cell loss resulting from stress and depression To further address this topic, we examined the expression of other neurotrophic-growth factors and related signaling pathways in the hippocampus in response to ECS using a custom growth factor microarray chip We report the regulation of several genes that are involved in growth factor and angiogenic-endothelial signaling, including neuritin, stem cell factor, vascular endothelial growth factor (VEGF), VGF (nonacronymic), cyclooxygenase-2, and tissue inhibitor of matrix metalloproteinase-1 Some of these, as well as other growth factors identified, including VEGF, basic fibroblast growth factor, and brain-derived neurotrophic factor, have roles in mediating neurogenesis and cell proliferation in the adult brain We also examined gene expression in the choroid plexus and found several growth factors that are enriched in this vascular tissue as well as regulated by ECS These data suggest that an amplification of growth factor signaling combined with angiogenic mechanisms could have an important role in the molecular action of ECS This study demonstrates the applicability of custom-focused microarray technology in addressing hypothesis-driven questions regarding the action of antidepressants
TL;DR: Caveolae are 50- to 100-nm cell-surface plasma membrane invaginations observed in terminally differentiated cells, which suggest an important role for caveolin-1 in the pathogenesis of cancer, atherosclerosis, and vascular disease.
Abstract: Caveolae are 50- to 100-nm cell-surface plasma membrane invaginations observed in terminally differentiated cells. They are particularly abundant in endothelial cells, where they are believed to play a major role in the regulation of endothelial vesicular trafficking and signal transduction. The use of caveolin-1–deficient mice has provided many new insights into the roles of caveolae and caveolin-1 in the regulation of endothelial cell function. These novel findings suggest an important role for caveolin-1 in the pathogenesis of cancer, atherosclerosis, and vascular disease.
TL;DR: It is shown that basic fibroblast growth factor and vascular endothelial growth factor differentially activate Raf, resulting in protection from distinct pathways of apoptosis in human endothelial cells and chick embryo vasculature, implicate Raf-1 as a pivotal regulator of endothelial cell survival during angiogenesis.
Abstract: Raf kinases have been linked to endothelial cell survival. Here, we show that basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) differentially activate Raf, resulting in protection from distinct pathways of apoptosis in human endothelial cells and chick embryo vasculature. bFGF activated Raf-1 via p21-activated protein kinase-1 (PAK-1) phosphorylation of serines 338 and 339, resulting in Raf-1 mitochondrial translocation and endothelial cell protection from the intrinsic pathway of apoptosis, independent of the mitogen-activated protein kinase kinase-1 (MEK1). In contrast, VEGF activated Raf-1 via Src kinase, leading to phosphorylation of tyrosines 340 and 341 and MEK1-dependent protection from extrinsic-mediated apoptosis. These findings implicate Raf-1 as a pivotal regulator of endothelial cell survival during angiogenesis.
TL;DR: Inactivation of the IR on endothelial cell has no major consequences on vascular development or glucose homeostasis under basal conditions, but alters expression of vasoactive mediators and may play a role in maintaining vascular tone and regulation of insulin sensitivity to dietary salt intake.
Abstract: Insulin receptors (IRs) on vascular endothelial cells have been suggested to participate in insulin-regulated glucose homeostasis. To directly address the role of insulin action in endothelial function, we have generated a vascular endothelial cell IR knockout (VENIRKO) mouse using the Cre-loxP system. Cultured endothelium of VENIRKO mice exhibited complete rearrangement of the IR gene and a more than 95% decrease in IR mRNA. VENIRKO mice were born at the expected Mendelian ratio, grew normally, were fertile, and exhibited normal patterns of vasculature in the retina and other tissues. Glucose homeostasis under basal condition was comparable in VENIRKO mice. Both eNOS and endothelin-1 mRNA levels, however, were reduced by approximately 30–60% in endothelial cells, aorta, and heart, while vascular EGF expression was maintained at normal levels. Arterial pressure tended to be lower in VENIRKO mice on both low- and high-salt diets, and on a low-salt diet VENIRKO mice showed insulin resistance. Thus, inactivation of the IR on endothelial cell has no major consequences on vascular development or glucose homeostasis under basal conditions, but alters expression of vasoactive mediators and may play a role in maintaining vascular tone and regulation of insulin sensitivity to dietary salt intake.
TL;DR: It is shown that RNA-cleaving phosphodiester-linked DNA-based enzymes (DNAzymes), targeting a specific motif in the 5′ untranslated region of early growth response (Egr-1) mRNA, inhibit EGr-1 protein expression, microvascular endothelial cell replication and migration, and microtubule network formation on basement membrane matrices.
Abstract: Current understanding of key transcription factors regulating angiogenesis is limited. Here we show that RNA-cleaving phosphodiester-linked DNA-based enzymes (DNAzymes), targeting a specific motif in the 5' untranslated region of early growth response (Egr-1) mRNA, inhibit Egr-1 protein expression, microvascular endothelial cell replication and migration, and microtubule network formation on basement membrane matrices. Egr-1 DNAzymes blocked angiogenesis in subcutaneous Matrigel plugs in mice, an observation that was independently confirmed by plug analysis in Egr-1-deficient animals, and inhibited MCF-7 human breast carcinoma growth in nude mice. Egr-1 DNAzymes suppressed tumor growth without influencing body weight, wound healing, blood coagulation or other hematological parameters. These agents inhibited endothelial expression of fibroblast growth factor (FGF)-2, a proangiogenic factor downstream of Egr-1, but not that of vascular endothelial growth factor (VEGF). Egr-1 DNAzymes also repressed neovascularization of rat cornea. Thus, microvascular endothelial cell growth, neovascularization, tumor angiogenesis and tumor growth are processes that are critically dependent on Egr-1.
TL;DR: It is suggested that activation of the angiopoietin/Tie-2 system may play a role in the ability of HIF-1 to induce hypervascularity without excessive permeability.
Abstract: Hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of vascular endothelial growth factor (VEGF) and other hypoxia-responsive genes. Transgenic expression of a constitutively stable HIF-1alpha mutant increases the number of vascular vessels without vascular leakage, tissue edema, or inflammation. This study aimed to investigate the molecular basis by which HIF-1 mediates the angiogenic response to hypoxia. In primary human endothelial cells, hypoxia, desferrioxamine, or infection with Ad2/HIF-1alpha/VP16, an adenoviral vector encoding a constitutively stable hybrid form of HIF-1alpha, increased the mRNA and protein levels of VEGF, angiopoietin-2 (Ang-2), and angiopoietin-4 (Ang-4). Infection with Ad2/CMVEV (a control vector expressing no transgene) had no effect. Angiopoietin-1 (Ang-1) expression was not detected in human endothelial cells. Ang-4 was also induced by hypoxia or Ad2/HIF-1alpha/VP16 in human cardiac cells, whereas Ang-1 expression remained unchanged. Recombinant Ang-4 protein protected endothelial cells against serum starvation-induced apoptosis and increased cultured endothelial cell migration and tube formation. Ad2/HIF-1alpha/VP16 stimulated endothelial cell proliferation and tube formation. Hypoxia- or Ad2/HIF-1alpha/VP16-induced tube formation was significantly reduced by a Tie-2 inhibitor. These results suggest that HIF-1 mediates the angiogenic response to hypoxia by upregulating the expression of multiple angiogenic factors. Ang-4 can function similarly as Ang-1 and substitute for Ang-1 to participate in hypoxia-induced angiogenesis. Activation of the angiopoietin/Tie-2 system may play a role in the ability of HIF-1 to induce hypervascularity without excessive permeability.
TL;DR: IFN-alpha confers its antitumor activity, at least in part, by its antiangiogenic activity, which results from Sp1- and/or Sp3-mediated inhibition of VEGF gene transcription.
Abstract: Effects of interferon alpha on vascular endothelial growth factor gene transcription and tumor angiogenesis.
TL;DR: This work found TNF-α to induce a decrease in stable tubulin content and partial dissolution of peripheral microtubule network as evidenced by anti-acetylated tubulin and anti–β-tubulin immunofluorescent staining, respectively.
Abstract: Tumor necrosis factor (TNF)-α, a major proinflammatory cytokine, triggers endothelial cell activation and barrier dysfunction which are implicated in the pathogenesis of pulmonary edema associated with acute lung injury syndromes. The mechanisms of TNF-α–induced vascular permeability are not completely understood. Our initial experiments demonstrated that TNF-α–induced decreases in transendothelial electrical resistance across human pulmonary artery endothelial cells are independent of myosin light chain phosphorylation catalyzed by either myosin light chain kinase or Rho kinase. We next assessed the involvement of another cytoskeletal component, the tubulin-based microtubule network, and found TNF-α to induce a decrease in stable tubulin content and partial dissolution of peripheral microtubule network as evidenced by anti-acetylated tubulin and anti–β-tubulin immunofluorescent staining, respectively. Microtubule-stabilizing agents, paclitaxel and epothilone B, significantly attenuated TNF-α–induced decr...
TL;DR: The data suggest that the carboxyl-terminal tail of VEGFR-3 provides important regulatory tyrosine phosphorylation sites with potential signal transduction capacity and that these sites are differentially used in ligand-induced homo- and heterodimeric receptor complexes.
TL;DR: The results suggest that the interaction between HIF-2α and endothelial Ets factors is required for the full transcriptional activation of Flk-1 in endothelial cells and may therefore represent a future target for the manipulation of angiogenesis.
TL;DR: The results indicate that at least some of the TEC within a tumor display abnormal characteristics in terms of survival and angiogenic properties and also indicate the presence of a functional autocrine pathway related to VEGF‐D.
Abstract: Knowledge on the functional properties of tumor-derived endothelial cells (TEC) can be relevant for the development of antiangiogenic therapeutic strategies. In the present study, we obtained and characterized endothelial cell lines from human renal carcinomas. TEC did not undergo senescence and showed constant expression of markers of endothelial activation and angiogenesis. In vitro, TEC, in contrast to normal endothelial cells, were resistant to apoptosis, proadhesive for renal carcinoma cells, and able to grow and organize in the absence of serum in persistent capillary-like structures. In vivo, TEC were able to grow in immunodeficient mice and to form vascular structures connected with the circulation. At a molecular level, gene array analysis showed an increased expression of genes involved in survival and cell adhesion compared with expression in normal microvascular endothelial cells. Moreover, expression of angiopoietin-1 and vascular endothelial growth factor (VEGF)-D and the Akt survival pathway were up-regulated. Inhibition of interaction of VEGFR-2 or VEGFR-3 with VEGF-D but not of Tie-2-angiopoietin-1 interaction with soluble receptors abrogated Akt activation and survival of TEC. These results indicate that at least some of the TEC within a tumor display abnormal characteristics in terms of survival and angiogenic properties and also indicate the presence of a functional autocrine pathway related to VEGF-D.
TL;DR: It is indicated that WAVE2-regulated actin reorganization might be required for proper cell movement and that a lack of functionalWAVE2 impairs angiogenesis in vivo.
Abstract: WAVE2, a protein related to Wiskott–Aldrich syndrome protein, is crucial for Rac-induced membrane ruffling, which is important in cell motility1,2,3,4. Cell movement is essential for morphogenesis, but it is unclear how cell movement is regulated or related to morphogenesis. Here we show the physiological functions of WAVE2 by disruption of the WAVE2 gene in mice. WAVE2 was expressed predominantly in vascular endothelial cells during embryogenesis. WAVE2-/- embryos showed haemorrhages and died at about embryonic day 10. Deficiency in WAVE2 had no significant effect on vasculogenesis, but it decreased sprouting and branching of endothelial cells from existing vessels during angiogenesis. In WAVE2-/- endothelial cells, cell polarity formed in response to vascular endothelial growth factor, but the formation of lamellipodia at leading edges and capillaries was severely impaired. These findings indicate that WAVE2-regulated actin reorganization might be required for proper cell movement and that a lack of functional WAVE2 impairs angiogenesis in vivo.
TL;DR: The mechanisms stimulating or inhibiting the differentiation of bone marrow-derived EPCs in vivo and the signals causing their adhesion, migration, and homing to sites of injured tissue are largely unknown at present.