The anti-angiogenic VEGF isoform VEGF165b transiently increases hydraulic conductivity, probably through VEGF receptor 1 in vivo.
Vascular endothelial growth factor (VEGF) is the principal agent that increases microvascular permeability during physiological and pathological angiogenesis. VEGF is differentially spliced to form two families of isoforms: VEGF(xxx), and VEGF(xxx)b. Whereas VEGF(165) stimulates angiogenesis, VEGF(165)b is anti-angiogenic. To determine the effect of VEGF(165)b on permeability, hydraulic conductivity (L(p)) was measured in individually perfused microvessels in the mesentery of frogs and rats. As with VEGF(165), VEGF(165)b increased L(p) in amphibian (2.4 +/- 0.3-fold) and mammalian (1.9 +/- 0.2-fold) mesenteric microvessels. A dose-response relationship showed that VEGF(165)b (EC(50), 0.65 pm) was approximately 25 times more potent than VEGF(165) (EC(50), 16 pm) in amphibian microvessels. VEGF(165) has been shown to increase permeability through VEGF receptor 2 (VEGF-R2) signalling. However, VEGF(165)b increased L(p) of frog vessels to the same extent in the presence of the VEGF-R2 inhibitor ZM323881, indicating that it does not increase permeability via VEGF-R2 signalling, and was inhibited by the VEGF receptor inhibitor SU5416 at doses that are specific for VEGF receptor 1 (VEGF-R1). VEGF(165)b, in contrast to VEGF(165), did not result in a sustained chronic increase in L(p). These results show that although VEGF(165)b is anti-angiogenic in the mesentery, it does signal in endothelial cells in vivo resulting in a transient, but not sustained, increase in microvascular L(p), probably through VEGF-R1.
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Microvascular Research Laboratories, Department of Physiology, Preclinical Veterinary School, Southwell Street, University of Bristol, Bristol BS2 8EJ, UK. dave.bates@bristol.ac.uk
Harper
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Bates
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D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008297:Male; D008643:Mesentery / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D020033:Protein Isoforms / Q000008:administration & dosage; D011898:Ranidae; D051381:Rats; D017208:Rats, Wistar; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1