Disease relevance of Vegfa

• Vegfa(delta/delta) mice were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death [1].
• The mean volume of ascites, number of tumor cells in ascites, and the peritoneal capillary permeability were significantly suppressed by VEGF-A nAb and KDR/Flk-1 nAb treatment [2].
• Despite the hypoxia, levels of HIF-1 alpha, a protein known to up-regulate VEGF-A, were reduced [3].
• Throughout a period of 14 days, in areas of cortical tubular atrophy and interstitial fibrosis, loss of VEGFR-2 and platelet endothelial cell adhesion molecule-expressing peritubular capillaries was preceded by marked decreases in VEGF-A transcript and protein levels [3].
• Tetralogy of fallot and alterations in vascular endothelial growth factor-A signaling and notch signaling in mouse embryos solely expressing the VEGF120 isoform [4].

High impact information on Vegfa

• Hypoxia stimulates angiogenesis through the binding of hypoxia-inducible factors to the hypoxia-response element in the vascular endothelial growth factor (Vegf) promotor [5].
• Our results indicate that chronic vascular insufficiency and, possibly, insufficient Vegf-dependent neuroprotection lead to the select degeneration of motor neurons [5].
• Here, we report that deletion of the hypoxia-response element in the Vegf promotor reduced hypoxic Vegf expression in the spinal cord and caused adult-onset progressive motor neuron degeneration, reminiscent of amyotrophic lateral sclerosis [5].
• Studies using hepatocyte-specific deletion of the Vegfa gene and hepatocyte-endothelial cell cocultures indicated that blockade of VEGF induced hepatic Epo by interfering with homeostatic VEGFR2-dependent paracrine signaling involving interactions between hepatocytes and endothelial cells [6].
• Bone marrow-derived DCs underwent endothelial-like differentiation ex vivo, migrated to blood vessels and promoted the growth of tumors expressing high levels of Vegf-A [7].

Chemical compound and disease context of Vegfa

• The D2R knockout mouse represents a unique animal model to study dopamine-resistant prolactinomas, and VEGF-A may be an alternative therapeutic target in this pathology [8].
• The purpose of this study was to determine the therapeutic potential of a VEGF/VPF receptor tyrosine kinase phosphorylation inhibitor, PTK 787, against PE formed by human lung adenocarcinoma (PC14PE6) cells [9].
• To test this hypothesis, we used the small molecule inhibitors SU5416 (an inhibitor for Vegf receptor) and SU6668 (an inhibitor for Vegf, Fgf and Pdgf receptors) alone and in combination with fractionated irradiation to treat C3H mice bearing SCC VII carcinomas [10].

Biological context of Vegfa

• Our study of Vegfa conditional knockout (CKO) mice provides new in-vivo evidence for two important functions of VEGFA in bone formation [11].
• Chondrocytes in these regions were found to upregulate expression of Vegfa in wild-type mice at the time when massive cell death occurred in the Vegfa CKO mice [11].
• In this study, we provide evidence that Vegfa gene expression is also regulated by activation of liver X receptors (LXRs) [12].
• Rather, LXR/retinoid X receptor heterodimers bound directly to a conserved hormone response element (LXRE) in the promoter of the murine and human Vegfa genes [12].
• Unlike Vegfa knockout mice, which die during embryogenesis, Vegfb(-/-) mice are healthy and fertile [13].

Anatomical context of Vegfa

• Therefore, Hhex expression in the ventral foregut endoderm and/or the endothelium is necessary for normal cardiovascular development in vivo, and one function of Hhex is to repress Vegfa levels during development [14].
• First, VEGFA plays a significant role in both early and late stages of cartilage vascularization, since Vegfa CKO mice showed delayed invasion of blood vessels into primary ossification centers and delayed removal of terminal hypertrophic chondrocytes [11].
• Distinct genetic interactions between multiple Vegf receptors are required for development of different blood vessel types in zebrafish [15].
• Vascular endothelial growth factor receptor 2 (VEGFR2/Flk-1)-positive cells derived from embryonic stem (ES) cells serve as vascular progenitors, which differentiate into endothelial cells (ECs) in the presence of VEGF-A [16].
• Surprisingly, unlike VEGF-A, VEGF-C did not increase leukocyte rolling or adhesion in tumor vessels [17].

Associations of Vegfa with chemical compounds

• Here, we report that elevated glucose inhibits EMT by reducing myocardial vascular endothelial growth factor A (VEGF-A) [18].
• Emodin inhibits vascular endothelial growth factor-A-induced angiogenesis by blocking receptor-2 (KDR/Flk-1) phosphorylation [19].
• High-dose ibuprofen decreased retinal VEGF levels and retinal VEGF164, VEGF120, and VEGFR-2 transcripts, resulting in a significant increase in the cecal period in 87% of rats at P14 [20].
• However, after 5-fluorouracil (5-FU) treatment, there was a rapid increase in plasma vascular endothelial growth factor A (VEGF-A) levels and expansion of Tie2-positive neovessels [21].
• Together, these observations provide new mechanistic insight into the dopamine-mediated inhibition of the activities of VPF/VEGF and suggest that endogenous neurotransmitter dopamine might be an important physiological regulator of VPF/VEGF activities in vivo [22].

Physical interactions of Vegfa

• In contrast, VEGF-A binds VEGFR1 and VEGFR2 and is an essential hemangiogenic factor [23].
• Nrp-1 also binds the VEGF-A splice isoform VEGF165, stimulates angiogenesis, and is necessary for vascular development in the mouse [24].

Regulatory relationships of Vegfa

• The use of pharmacological inhibitors or genetic inhibition revealed that both the phosphatidylinositol 3-kinase (PI3K)/Akt and p38 signaling pathways were potentially required for diosgenin-induced HIF-1 activation and subsequent VEGF-A up-regulation [25].
• These data suggest that VEGF-A-induced up-regulation of Tie2 expression on the regenerating vasculature after BM suppression supports the assembly of sinusoidal endothelial cells, thereby promoting reconstitution of hematopoiesis [21].
• These effects were specific for BMPs, as TGF beta inhibited osteoblast differentiation and angiogenesis while stimulating VEGF-A production [26].
• Autocrine VEGF-A system in podocytes regulates podocin and its interaction with CD2AP [27].
• Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A [26].

Other interactions of Vegfa

• Elevated glucose inhibits VEGF-A-mediated endocardial cushion formation: modulation by PECAM-1 and MMP-2 [18].
• Vascular endothelial growth factor A (VEGF-A) is involved in guidance of VEGF receptor-positive cells to the anterior portion of early embryos [28].
• Furthermore, VEGF-C overexpression elevated vascular permeability in T241 tumors, but not in VEGF-A-/- tumors [17].
• Interestingly, the extensive cell death seen in Vegfa CKO null bones had a striking similarity to the cell death phenotype observed when hypoxia-inducible factor 1 alpha (Hif1a) expression was abolished in developing cartilage [11].
• A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels [14].

Analytical, diagnostic and therapeutic context of Vegfa

• In this study, for the first time, we investigated about the localization of VEGF-A, VEGFR-2 and Ang-2 in the choroid plexuses of the adult mouse by Western blot and immunohistochemistry [29].
• Using a novel system for microinjecting and electroporating plasmid expression constructs into murine organ cultures, it has been demonstrated that Vegfa expression in the mesenchyme is regulated by Wt1 [30].
• VEGF-A secretion was assessed by ELISA and Western analysis [27].
• Results in clinical trials of VEGF-A as a therapeutic agent have fallen short of high expectations because of serious edematous side effects caused by its activity in promoting vascular permeability [31].
• Our data demonstrate that tight regulation of VEGF-A signaling is critical for establishment and maintenance of the glomerular filtration barrier and strongly supports a pivotal role for VEGF-A in renal disease [32].

References