Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.

The biology of VEGF and its receptors.

The establishment of a vascular supply is required for organ development and differentiation as well as for tissue repair and reproductive functions in the adult1 Neovascularization (angiogenesis) is also implicated in the pathogenesis of a number of disorders These include: proliferative retinopathies, age-related macular degeneration, tumors, rheumatoid arthritis, and psoriasis1,2 A strong correlation has been noted between density of microvessels in primary breast cancers and their nodal metastases and patient survival3 Similarly, a correlation has been reported between vascularity and invasive behavior in several other tumors4–6

The biology of vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a major inducer of VEGF gene transcription. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high-affinity VEGF receptors. The role of VEGF in developmental angiogenesis is emphasized by the finding that loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF is critical also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with various VEGF inhibitors in a variety of malignancies are ongoing. Very recently, an anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.

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Vascular endothelial growth factor: basic science and clinical progress.

Role of endothelium in responses of vascular smooth muscle.

Indirect evidence suggests accelerated degradation of endothelium-derived nitric oxide (ENDO) by superoxide anion (O2-) in hypercholesterolemic vessels (HV) To directly measure O2- production by normal vessels (NV) and HV, we used an assay for O2- based on the chemiluminescence (CL) of lucigenin (L) HV (1 mo cholesterol-fed rabbits) produced threefold more O2- than NV (147 +/- 020 nM/mg tissue/min, n = 7 vs 052 +/- 005 nmol/mg tissue/min, n = 8, P < 0001) Endothelial removal increased O2- production in NV (073 +/- 008, n = 6, P < 005), while decreasing it in HV (076 +/- 015, n = 5, P < 005) There was no difference between denuded HV and denuded NV Oxypurinol, a noncompetitive inhibitor of xanthine oxidase, normalized O2- production in HV, but had no effect in NV In separate isometric tension studies treatment with oxypurinol improved acetylcholine induced relaxations in HV, while having no effect on responses in normal vessels Oxypurinol did not alter relaxations to nitroprusside Thus, the endothelium is a source of O2- in hypercholesterolemia probably via xanthine oxidase activation Increased endothelial O2- production in HV may inactivate endothelium-derived nitric oxide and provide a source for other oxygen radicals, contributing to the early atherosclerotic process

/pdf/hypercholesterolemia-increases-endothelial-superoxide-anion-1rnwngjon2.pdf

Hypercholesterolemia increases endothelial superoxide anion production.

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), has recently been shown to increase cytosolic free calcium in endothelial cells. In the present study, we investigated the coronary vascular effects of recombinant human and native guinea pig VEGF/VPF in isolated canine coronary arteries in the presence and absence of intimal endothelium, indomethacin, and NG-monomethyl-L-arginine, a competitive nitric oxide synthase inhibitor. Addition of recombinant VEGF/VPF (1-660 pM) in coronary arteries that had been previously contracted with prostaglandin F2 alpha induced a slow, dose-dependent relaxation, reaching a maximum of -59.1 +/- 6.7% (mean +/- SE, n = 19). Mechanical disruption of the intimal endothelium completely abolished the observed relaxation. No direct vascular effect of recombinant VEGF/VPF on the endothelium-disrupted coronary arteries was noted. Pretreatment of endothelium-intact coronary arteries with 5 microM of indomethacin did not alter the observed relaxation (-57.3 +/- 7.0%, n = 18), whereas pretreatment with either NG-monomethyl-L-arginine or 10 microM of genistein, a known inhibitor of tyrosine kinase, significantly inhibited the relaxation. Addition of native VEGF/VPF (1-100 pM) also induced an endothelium-dependent relaxation in the isolated coronary arteries. Heating of recombinant VEGF/VPF (70 degrees C, 25 min) or prior incubation with a specific antibody raised against a VEGF/VPF peptide completely abolished the relaxation. Finally, recombinant VEGF/VPF stimulated a slow rise in cytosolic free calcium in cultured human endothelial cells that was qualitatively similar to that of native VEGF/VPF.(ABSTRACT TRUNCATED AT 250 WORDS)

Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries.

Exogenous thrombin produced a biphasic response (a potent dose-related vasodilatation followed by vasoconstriction) in nonischemic canine coronary arteries. The vasodilatation was not blocked by propranolol, atropine, or indomethacin, but was completely blocked by heparin or denudation of the intimal endothelial cells. A similar loss of vasodilating response to thrombin occurred in ischemic coronary arteries with a concomitant enhancement of vasoconstriction. This study indicates that altered responses to thrombin in coronary arteries with damaged endothelium may play an important role in the pathogenesis of coronary vasospasm.

Coronary vascular reactivity after acute myocardial ischemia.

https://www.gastrojournal.org/article/S0016-5085(97)00388-0/pdf

The role of endothelial nitric oxide synthase in the pathogenesis of a rat model of hepatopulmonary syndrome.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.20244

The role of endothelin-1 and the endothelin B receptor in the pathogenesis of hepatopulmonary syndrome in the rat

The present experiments were designed to determine whether or not endothelium-dependent contractions can be evoked in the aorta of the mouse, and if so, whether or not deleting the COX1 gene affects the response. Sex differences in the response were also examined. Rings of murine aorta were suspended in a Halpern-Mulvany myograph for recording of isometric force. In the aorta of the male wild type C57BL/b6 mice (36-40 weeks old), both acetylcholine and the calcium ionophore caused endothelium-dependent increases in force in the presence of L-NAME, and these were inhibited by valeryl salicylate (a selective COX1 inhibitor) and S18886 (a selective antagonist of TP receptors). Such endothelium-dependent contraction was absent in the aorta of COX1 knockout mice and present in that of COX2 knockout mice. Similar results were obtained in aortas of female wild-type, COX2 and COX1 knockout mice. These experiments reveal the existence of EDCF-mediated contractions in arteries of the mouse. These contractions, as in the aorta of the spontaneously hypertensive rat, are caused by endogenous agonists(s) of TP receptors produced by cyclooxygenase 1, because they are observed in the aortas of COX2 knockout mice but not in aortas of COX1 knockout mice. The present study provides direct evidence that COX1 is indeed the isoform of cyclooxygenase responsible for the production of EDCF.

David D. Ku

Papers

Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries.

Coronary vascular reactivity after acute myocardial ischemia.

The role of endothelial nitric oxide synthase in the pathogenesis of a rat model of hepatopulmonary syndrome.

The role of endothelin-1 and the endothelin B receptor in the pathogenesis of hepatopulmonary syndrome in the rat

Endothelium-dependent contractions occur in the aorta of wild-type and COX2-/- knockout but not COX1-/- knockout mice.