© 1997 American Heart Association, Inc.
Articles |
Vascular Endothelial Growth Factor/Vascular Permeability Factor Produces Nitric Oxide–Dependent Hypotension
Evidence for a Maintenance Role in Quiescent Adult Endothelium
From the Departments of Medicine (Cardiology), Surgery (Cardiovascular; M.H., J.F.S.), and Biomedical Research, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass.
Correspondence to Jeffrey M. Isner, MD, St Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail jisner{at}opal.tufts.edu
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 µg 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 µg
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
-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.
Key Words: endothelium • angiogenesis • nitric oxide
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