Vascular endothelial growth factor A

About: Vascular endothelial growth factor A is a research topic. Over the lifetime, 15203 publications have been published within this topic receiving 1271498 citations. The topic is also known as: vascular endothelial growth factor A & vascular endothelial growth factor A165.

Hypoxia-Inducible Factor-1 in Physiological and Pathophysiological Angiogenesis: Applications and Therapies

Abstract: The cardiovascular system ensures the delivery of oxygen and nutrients to all cells, tissues, and organs. Under extended exposure to reduced oxygen levels, cells are able to survive through the transcriptional activation of a series of genes that participate in angiogenesis, glucose metabolism, and cell proliferation. The oxygen-sensitive transcriptional activator HIF-1 (hypoxia-inducible factor-1) is a key transcriptional mediator of the response to hypoxic conditions. The HIF-1 pathway was found to be a master regulator of angiogenesis. Whether the process is physiological or pathological, HIF-1 seems to participate in vasculature formation by synergistic correlations with other proangiogenic factors such as VEGF (vascular endothelial growth factor), PlGF (placental growth factor), or angiopoietins. Considering the important contributions of HIF-1 in angiogenesis and vasculogenesis, it should be considered a promising target for treating ischaemic diseases or cancer. In this review, we discuss the roles of HIF-1 in both physiological/pathophysiological angiogenesis and potential strategies for clinical therapy.

The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues

Abstract: Diabetes is associated with poor outcomes following acute vascular occlusive events. This results in part from a failure to form adequate compensatory microvasculature in response to ischemia. Since vascular endothelial growth factor (VEGF) is an essential mediator of neovascularization, we examined whether hypoxic up-regulation of VEGF was impaired in diabetes. Both fibroblasts isolated from type 2 diabetic patients, and normal fibroblasts exposed chronically to high glucose, were defective in their capacity to up-regulate VEGF in response to hypoxia. In vivo, diabetic animals demonstrated an impaired ability to increase VEGF production in response to soft tissue ischemia. This resulted from a high glucose-induced decrease in transactivation by the transcription factor hypoxia-inducible factor-1α (HIF-1α), which mediates hypoxia-stimulated VEGF expression. Decreased HIF-1α functional activity was specifically caused by impaired HIF-1α binding to the coactivator p300. We identify covalent modification of p300 by the dicarbonyl metabolite methylglyoxal as being responsible for this decreased association. Administration of deferoxamine abrogated methylglyoxal conjugation, normalizing both HIF-1α/p300 interaction and transactivation by HIF-1α. In diabetic mice, deferoxamine promoted neovascularization and enhanced wound healing. These findings define molecular defects that underlie impaired VEGF production in diabetic tissues and offer a promising direction for therapeutic intervention.

The Tie-2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism

Abstract: The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the endothelial receptor tyrosine kinase Tie-2, which controls vascular assembly and endothelial quiescence. The largely complementary phenotypes of Ang-1-deficient mice and Ang-2-overexpressing mice have led to an antagonistic model in which Ang-1 acts as Tie-2-activating agonist and Ang-2 acts as a Tie-2-inhibiting antagonist. To date, no mechanistic equivalent of the antagonistic Ang-1/Ang-2 model has been established and the mechanisms of Ang-2 function in particular remain mysterious. We have studied the effector functions of Ang-1 and Ang-2 on quiescent endothelial cells using a three-dimensional co-culture model of endothelial cells and smooth-muscle cells. Endothelial-cell monolayer integrity in this model is dependent on Tie-2 signaling, as evidenced by detaching endothelial cells following exposure to the small molecular weight Tie-2 inhibitor A-422885.66, which cannot be overcome by exogenous Ang-1. Accordingly, exogenous Ang-2 rapidly destabilizes the endothelial layer, which can be observed within 30-60 minutes and leads to prominent endothelial-cell detachment within 4 hours. Exogenous Ang-2-mediated endothelial-cell detachment can be rescued by Ang-1, soluble Tie-2 and vascular endothelial growth factor. Similar findings were obtained in an umbilical-vein explant model. Ang-2 is mainly produced by endothelial cells and therefore acts primarily in an autocrine manner. Thus, stimulated release of endogenous Ang-2 or overexpression of Ang-2 in endothelial cells perturbs co-culture spheroid integrity, which can be rescued by exogenous Ang-1 and vascular endothelial growth factor. However, autocrine Ang-2-mediated endothelial-cell detachment cannot be blocked by soluble Tie-2. Taken together, the data demonstrate for the first time the antagonistic Ang-1/Ang-2 concept in a defined cellular model and identify Ang-2 as a rapidly acting autocrine regulator of the endothelium that acts through an internal autocrine loop mechanism.

Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo.

Abstract: A central tenet of fibrinolysis is that tissue plasminogen activator-dependent (t-PA- dependent) conversion of plasminogen to active plasmin requires the presence of the cofactor/substrate fibrin. However, previous in vitro studies have suggested that the endothelial cell surface protein annexin II can stimulate t-PA-mediated plasminogen activation in the complete absence of fibrin. Here, homozygous annexin II-null mice displayed deposition of fibrin in the microvasculature and incomplete clearance of injury-induced arterial thrombi. While these animals demonstrated normal lysis of a fibrin-containing plasma clot, t-PA-dependent plasmin generation at the endothelial cell surface was markedly deficient. Directed migration of annexin II-null endothelial cells through fibrin and collagen lattices in vitro was also reduced, and an annexin II peptide mimicking sequences necessary for t-PA binding blocked endothelial cell invasion of Matrigel implants in wild-type mice. In addition, annexin II-deficient mice displayed markedly diminished neovascularization of fibroblast growth factor-stimulated cornea and of oxygen-primed neonatal retina. Capillary sprouting from annexin II-deficient aortic ring explants was markedly reduced in association with severe impairment of activation of metalloproteinase-9 and -13. These data establish annexin II as a regulator of cell surface plasmin generation and reveal that impaired endothelial cell fibrinolytic activity constitutes a barrier to effective neoangiogenesis.