VASCULAR ENDOTHELIAL GROWTH-FACTOR INDUCES EDRF-DEPENDENT RELAXATION IN CORONARY-ARTERIES

Vascular endothelial growth factor (VEGF), also known as vascular perm eability factor (VPF), has recently been shown to increase cytosolic f ree calcium in endothelial cells. In the present study, we investigate d 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 N(G)-monomethyl-L-a rginine, a competitive nitric oxide synthase inhibitor. Addition of re combinant VEGF/VPF (1-660 pM) in coronary arteries that had been previ ously contracted with prostaglandin F2alpha induced a slow, dose-depen dent relaxation, reaching a maximum of -59.1 +/- 6.7% (means +/- SE, n = 19). Mechanical disruption of the intimal endothelium completely ab olished the observed relaxation. No direct vascular effect of recombin ant VEGF/VPF on the endothelium-disrupted coronary arteries was noted. Pretreatment of endothelium-intact coronary arteries with 5 muM of in domethacin did not alter the observed relaxation (-57.3 +/- 7.0%, n = 18), whereas pretreatment with either N(G)-monomethyl-L-arginine or 10 muM 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 pr ior incubation with a specific antibody raised against a VEGF/VPF pept ide completely abolished the relaxation. Finally, recombinant VEGF/VPF stimulated a slow rise in cytosolic free calcium in cultured human en dothelial cells that was qualitatively similar to that of native VEGF/ VPF. Collectively, these results show that VEGF/VPF, a tyrosine kinase -coupled endothelial growth factor, induces endothelium-dependent rela xation via the Ca2+-dependent synthesis and/or release of endothelium- derived relaxing factor.