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: VEGFxxx, and VEGFxxxb. Whereas VEGF165 stimulates angiogenesis, VEGF165b is anti-angiogenic. To determine the effect of VEGF165b on permeability, hydraulic conductivity (Lp) was measured in individually perfused microvessels in the mesentery of frogs and rats. As with VEGF165, VEGF165b increased Lp in amphibian (2.4 ± 0.3-fold) and mammalian (1.9 ± 0.2-fold) mesenteric microvessels. A dose–response relationship showed that VEGF165b (EC50, 0.65 pm) was approximately 25 times more potent than VEGF165 (EC50, 16 pm) in amphibian microvessels. VEGF165 has been shown to increase permeability through VEGF receptor 2 (VEGF-R2) signalling. However, VEGF165b increased Lp 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). VEGF165b, in contrast to VEGF165, did not result in a sustained chronic increase in Lp. These results show that although VEGF165b is anti-angiogenic in the mesentery, it does signal in endothelial cells in vivo resulting in a transient, but not sustained, increase in microvascular Lp, probably through VEGF-R1.