Vascular endothelial growth factor increases microvascular permeability via a Ca2+-dependent pathway

We tested the hypothesis that vascular endothelial growth factor (VEGF) increases microvascular permeability by increasing calcium influx into endothelial cells forming the vessel walls. We measured microvessel hydraulic conductivity (L-p) in isolated perfused MS-222-anesthetized frog mesenteric microvessels during perfusion with VEGF under conditions that attenuate calcium influx. VEGF increased L-p during a second successive perfusion in the same microvessel by 7.8-fold, which was not significantly different from that brought about by an initial application of VEGF (5.0-fold). However, under depolarizing conditions, the increase in L-p was reduced from 11.1- to 5.6-fold when depolarized to -10 mV (58 mM K+) and to 2.8-fold when depolarized to 0 mV (100 mM K+). Attenuating calcium influx by the addition of nickel ions resulted in a similar attenuation of the increase in L-p (from 13- to 2.5-fold). VEGF also increased the intracellular calcium concentration in endothelial cells of perfused microvessels as determined by measurement with fura 2. We therefore conclude that VEGF increases L-p by increasing calcium influx.