Dd. Ku et al., VASCULAR ENDOTHELIAL GROWTH-FACTOR INDUCES EDRF-DEPENDENT RELAXATION IN CORONARY-ARTERIES, The American journal of physiology, 265(2), 1993, pp. 80000586-80000592
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.