Disease relevance of VEGF

• In spite of the enhanced VEGF/PEDF ratios resulting from hypoxia, conditioned media of Müller cells failed to stimulate additional proliferation of retinal endothelial cells [1].
• Increased expression of vascular endothelial growth factor (VEGF) has been correlated with increased oxidative stress and formation of peroxynitrite in numerous disease conditions, including diabetic microangiopathy, tumor angiogenesis, and atherosclerosis [2].
• It has been reported that vascular endothelial growth factor (VEGF) and its receptors play an important role in the destruction of articular cartilage in osteoarthritis through increased production of matrix metalloproteinases [3].
• Finally, transfection of control and irradiated cells with a replication-deficient TGF-beta1 adenovirus before irradiation resulted in an increase in cellular production of TGF-beta1 protein and VEGF [4].
• Targeting VEGF expression with specific pharmacological agents, such as antioxidants and PKC inhibitors, may prove efficacious for the treatment of diabetic retinopathy [5].

Psychiatry related information on VEGF

• The effect of vascular endothelial growth factor on a rat model of traumatic arteriogenic erectile dysfunction [6].

High impact information on VEGF

• However, unlike VEGF, EG-VEGF failed to promote angiogenesis in the cornea or skeletal muscle [7].
• VEGF is a heparin-binding growth factor specific for vascular endothelial cells that is able to induce angiogenesis in vivo [8].
• Complementary DNA clones for bovine and human VEGF were isolated from cDNA libraries prepared from FC and HL60 leukemia cells, respectively [8].
• AGEs may participate in the pathogenesis of diabetic retinopathy through their ability to increase retinal VEGF gene expression [9].
• In vitro, AGEs increased VEGF mRNA and secreted protein in human RPE and bovine vascular smooth muscle cells [9].

Chemical compound and disease context of VEGF

• Fifth, pericytes expressed the gene for fms-like tyrosine kinase 1 (flt1) as the predominant form of VEGF receptor, and tyrosine phosphorylation of this receptor protein was enhanced when pericytes were exposed to hypoxia, as it was when cells were exposed to VEGF [10].
• In conclusion, NAD(P)H oxidase activity is required for hypoxia-stimulated increases in VEGF expression and retinal neovascularization [11].
• Treatment of mice with apocynin blocked ischemia-induced increases in oxidative stress, normalized VEGF expression, and prevented retinal neovascularization [11].
• These data suggest that hypoxia induces an initial decline in KDR mRNA levels and VEGF binding sites as mediated through adenosine binding to the A2R [12].
• Induction of integrin alphav by VEGF and hypoxia was confirmed in the protein level [13].

Biological context of VEGF

• Furthermore, VEGF stimulation of BAECs or COS-7 cells transiently transfected with Flk-1 results in the phosphorylation of the ubiquitin ligase Cbl, the enhanced association of Cbl with Flk-1, and the relocalization of Cbl to vesicular structures in BAECs [14].
• Furthermore, overexpression of constitutive active Akt was sufficient to induce CTGF gene expression, and inhibition of Akt activation by overexpressing dominant negative mutant of Akt abolished the VEGF-induced CTGF expression [15].
• These results imply that TGF-beta 1 is a major regulator of the VEGF/Flk-1 signal transduction pathway in endothelial cells [16].
• In our study, VEGF increased CTGF mRNA levels in a time- and concentration-dependent manner in bovine retinal endothelial cells and pericytes, without the need of new protein synthesis and without altering mRNA stability [15].
• TGF-beta activation may, therefore, be prerequisite for hypoxia-induced up-regulation of VEGF and stimulation of angiogenesis in vivo [17].

Anatomical context of VEGF

• Vessel loss is associated with oxygen-induced suppression of vascular endothelial growth factor (VEGF) and with pericyte (vascular smooth muscle cell) dropout [18].
• Here we show that Flk-1 is rapidly down-regulated following VEGF stimulation of bovine aortic endothelial cells (BAECs) [14].
• Overexpression of Cbl in COS-7 cells enhances VEGF-induced ubiquitination of Flk-1, whereas a Cbl mutant lacking the ubiquitin ligase RING finger domain, 70Z/3-Cbl, does not [14].
• Here we demonstrate the effects of hypoxia on the expression of both TGF-beta and VEGF by retinal glial cells [17].
• Inhibition of Akt-phosphatidylinositol 3-kinase with wortmannin blocks both 20-HETE and VEGF-induced relaxation of pulmonary arteries, supporting the functional contribution of Akt phosphorylation to the vasoactive actions of both agents [19].

Associations of VEGF with chemical compounds

• Vascular endothelial growth factor (VEGF)-A165-induced prostacyclin synthesis requires the activation of VEGF receptor-1 and -2 heterodimer [20].
• In this study we tested the hypothesis that peroxynitrite stimulates VEGF expression [2].
• Both 20-HETE and VEGF increase the phosphorylation of eNOS at serine 1179 and Akt at serine 473 [19].
• The specific PPAR-gamma inhibitor GW9662 suppressed ox-LDL-induced VEGF expression [3].
• The increase in PlGF expression could be totally abolished by blocking VEGFR-2, and in the case of glucose by neutralising VEGF [21].

Physical interactions of VEGF

• BAPTA-AM inhibited VEGF- but not insulin-induced eNOS-HSP90-Akt complex formation and eNOS phosphorylation [22].
• In conclusion, our data demonstrate that VEGF binding to the KDR receptor tyrosine kinase results in an increase in KDR receptor gene transcription and protein expression [23].
• We investigated the effect of increased VEGF expression in the retina using tissue-specific, gain-of-function transgenic mice in which the bovine rhodopsin promoter is coupled to the gene for human VEGF [24].
• Northern blot analysis and 125I-VEGF binding analysis were used to identify hypoxia-induced alterations of VEGF receptor at mRNA and protein levels [12].
• PURPOSE: To investigate effects of vascular endothelial growth factor (VEGF) on glucose transport and GLUT1 glucose transporter expression in primary bovine retinal endothelial cell (BREC) cultures [25].

Regulatory relationships of VEGF

• Exposure of Müller cells to VEGF suppressed PEDF release in a dose-dependent manner [1].
• Moreover, transduction of endothelial cells with dominant-negative STAT3 abrogated the peroxynitrite-induced increase in VEGF mRNA [2].
• The CYP4 inhibitor dibromododecynyl methyl sulfonamide (DDMS) blocks VEGF-induced phosphorylation of eNOS [19].
• In endothelial cells, VEGF (100 ng/ml) and glucose (15 mM) induced an increase in expression of PlGF at both the mRNA and protein level while no effect was observed for pericytes [21].
• Oxidized LDL binding to LOX-1 upregulates VEGF expression in cultured bovine chondrocytes through activation of PPAR-gamma [3].

Other interactions of VEGF

• These results show that TGF-beta 1 exerts a biphasic effect on bFGF- and VEGF-induced angiogenesis in vitro [26].
• Peroxynitrite increases VEGF expression in vascular endothelial cells via STAT3 [2].
• Furthermore, it was found that treatment of Muller cells with exogenous TGF-beta under either hypoxia or normoxia increases VEGF expression in a time- and dose-dependent fashion [17].
• We have demonstrated that VEGF-induced dilation of bovine pulmonary arteries is associated with activation of cytochrome P-450 family 4 (CYP4) enzymes and eNOS [19].
• In contrast with TSP, VEGF expression increased during growth and development of the follicle [27].

Analytical, diagnostic and therapeutic context of VEGF

• To define the molecular mechanisms involved, the effect of peroxynitrite was determined on the activation of two transcription factors known to regulate VEGF expression during hypoxia and tumor angiogenesis-signal transducer and activator of transcription 3 (STAT3) and hypoxia-inducible factor-1 (HIF-1) [2].
• Adsorption of MCM by specific antibodies as well as Western and Northern blot analysis indicated that stimulating and inhibitory activities of MCM are due to the presence of VEGF and TGF-beta, respectively [17].
• The expression and quantities of VEGF and TGF-beta (active vs. latent form) were determined by immuno-adsorption, Western or Northern blotting, and ELISA [17].
• In this study, retinal microvascular endothelial cells and pericytes were exposed to varying concentrations of VEGF and glucose and PlGF expression measured by RT-PCR and Western blotting [21].
• Using applications of the polymerase chain reaction (PCR) technique, cDNA clones have been isolated encoding bovine vascular endothelial growth factor (VEGF), a mitogen with specificity for vascular endothelial cells [28].

References