Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries.
Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), has recently been shown to increase cytosolic free calcium in endothelial cells. In the present study, we investigated 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 NG-monomethyl-L-arginine, a competitive nitric oxide synthase inhibitor. Addition of recombinant VEGF/VPF (1-660 pM) in coronary arteries that had been previously contracted with prostaglandin F2 alpha induced a slow, dose-dependent relaxation, reaching a maximum of -59.1 +/- 6.7% (mean +/- SE, n = 19). Mechanical disruption of the intimal endothelium completely abolished the observed relaxation. No direct vascular effect of recombinant VEGF/VPF on the endothelium-disrupted coronary arteries was noted. Pretreatment of endothelium-intact coronary arteries with 5 microM of indomethacin did not alter the observed relaxation (-57.3 +/- 7.0%, n = 18), whereas pretreatment with either NG-monomethyl-L-arginine or 10 microM 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 prior incubation with a specific antibody raised against a VEGF/VPF peptide completely abolished the relaxation. Finally, recombinant VEGF/VPF stimulated a slow rise in cytosolic free calcium in cultured human endothelial cells that was qualitatively similar to that of native VEGF/VPF.(ABSTRACT TRUNCATED AT 250 WORDS)
Ku
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Department of Pharmacology, University of Alabama at Birmingham 35294.
Zaleski
J K
JK
Liu
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Brock
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TA
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D004285:Dogs; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D008222:Lymphokines / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D009994:Osmolar Concentration; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014664:Vasodilation / Q000502:physiology*
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D009569:Nitric Oxide; D002118:Calcium