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1 Department of Surgery, UMDNJ- New Jersey Medical School, Newark, NJ, USA
2 Department of Pharmacology & Physiology, UMDNJ-New Jersey Medical School, Newark, NJ, USA
* To whom correspondence should be addressed. E-mail: duran{at}umdnj.edu.
Vascular endothelial growth factor (VEGF) induces mild vasodilation and strong increases in microvascular permeability. Using intravital microscopy and digital integrated optical intensity (IOI) image analysis, we tested - in the hamster cheek pouch microcirculation - the hypothesis that differential signaling pathways in arterioles and venules represent an in vivo regulatory mechanism in the control of vascular diameter and permeability. The experimental design involved blocking specific signaling molecules and simultaneously assessing VEGF-induced changes in arteriolar diameter and microvascular transport of FITC-dextran-150. Inhibition of Akt (indirectly via PI-3K with LY294002 or wortmannin) or protein kinase C (PKC) with bisindolylmaleimide (BIM) reduced VEGF-induced hyperpermeability. However, PI-3K/Akt inhibition enhanced/attenuated the early/late phases, respectively, of VEGF-induced vasodilation, while blocking PKC had no effect. Inhibition of ERK-1/2 (with PD98059 or AG126) also reduced VEGF-induced hyperpermeability, but did not block VEGF-induced vasodilation. Blockade of eNOS (L-NMMA) inhibited VEGF-induced changes in both permeability and diameter. Furthermore, immunofluorescence studies with human umbilical vein endothelial cells (HUVEC) revealed that BIM, PD98059, and L-NMMA attenuate VEGF-induced reorganization of vascular endothelial (VE)-cadherin. Our data demonstrate that 1) eNOS is a common convergence pathway for VEGF-induced changes in arteriolar diameter and microvascular permeability; 2) PKC and ERK-1/2 do not play a major role in VEGF-induced vasodilation in the hamster cheek pouch microcirculation, 3) Akt, PKC and ERK-1/2 are elements of the signaling cascade that regulates VEGF-stimulated microvascular hyperpermeability. Our data provide evidence for differential signaling as a regulatory step in VEGF-stimulated microvascular dynamics.
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