title: Vascular endothelial growth factor/vascular permeability factor produces nitric oxide-dependent hypotension. Evidence for a maintenance role in quiescent adult endothelium.
abstract: In vitro studies suggest that vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) may stimulate release of nitric oxide (NO) from endothelial cells. To investigate the hemodynamic consequences of recombinant VEGF/VPF administered in vivo, recombinant human VEGF/VPF was administered as a bolus dose of 500 micrograms to anesthetized (n = 6) or conscious (n = 5) New Zealand White rabbits, as well as anesthetized rabbits with diet-induced hypercholesterolemia (HC; n = 7). Anesthetized Yorkshire farm pigs (no specific dietary pretreatment) were studied before and after receiving 500 micrograms intravenous (IV; n = 5) or intracoronary (IC; n = 5) VEGF/VPF. In anesthetized, normal rabbits, mean arterial pressure (MAP) fell by 20.5 +/- 1.4% (P < .05 versus baseline) within 3 minutes after IV VEGF/VPF. Pretreatment with N omega-nitro-L-arginine caused a significant inhibition of VEGF/VPF-induced hypotension. In conscious, normal rabbits, VEGF/VPF produced a consistent though lesser reduction in MAP. The fall in MAP induced by VEGF/VPF in anesthetized, HC rabbits (21.5 +/- 2.5% from baseline) was no different from that observed in normal anesthetized rabbits. In pigs, both IV and IC administration of VEGF/VPF produced a prompt reduction in MAP. Heart rate increased, while cardiac output, stroke volume, left atrial pressure, and total peripheral resistance all declined to a similar, statistically significant degree in both IV and IC groups. Epicardial echocardiography disclosed neither global nor segmental wall motion abnormalities in response to VEGF/VPF. We conclude that (1) VEGF/VPF-stimulated release of NO, previously suggested in vitro, occurs in vivo; (2) this finding suggests that functional VEGF/VPF receptors are present on quiescent adult endothelium, consistent with a maintenance function for VEGF/VPF, which may include regulation of NO; and (3) the preserved response of HC rabbits suggests that endothelial cell receptors for VEGF/VPF are spared in the setting of hypercholesterolemia.
authors.affiliation: Department of Medicine (Cardiology), St Elizabeth's Medical Center, Tufts University School of Medicine, MA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Horowitz
authors.forename: A
authors.initials: A
authors.lastname: Rivard
authors.forename: R
authors.initials: R
authors.lastname: van der Zee
authors.forename: M
authors.initials: M
authors.lastname: Hariawala
authors.forename: D D
authors.initials: DD
authors.lastname: Sheriff
authors.forename: D D
authors.initials: DD
authors.lastname: Esakof
authors.forename: G M
authors.initials: GM
authors.lastname: Chaudhry
authors.forename: J F
authors.initials: JF
authors.lastname: Symes
authors.forename: J M
authors.initials: JM
authors.lastname: Isner
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D002791:Cholesterol, Dietary / Q000633:toxicity; D004036:Diet, Atherogenic; D004452:Echocardiography; D016228:Endothelial Growth Factors / Q000494:pharmacology / Q000633:toxicity*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006937:Hypercholesterolemia / Q000209:etiology / Q000503:physiopathology; D007022:Hypotension / Q000139:chemically induced* / Q000503:physiopathology; D008222:Lymphokines / Q000494:pharmacology / Q000633:toxicity*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D011817:Rabbits; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000502:physiology; D017978:Receptors, Growth Factor / Q000187:drug effects / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor; D011994:Recombinant Proteins / Q000494:pharmacology / Q000633:toxicity; D012636:Secretory Rate / Q000187:drug effects; D013552:Swine; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014664:Vasodilation / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D002791:Cholesterol, Dietary; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019335:Nitroarginine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor