Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1156-1161
© 1999 American Heart Association, Inc.
Vascular Biology |
Role of Endothelial Nitric Oxide Synthase in Endothelial Cell Migration
Presented in part at the First Japan–US Joint Meeting on Vascular Biology, Kobe, Japan, August 30–31, 1998.
From the Departments of Medicine (Cardiology) and Biomedical Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass. Current address for T. Murohara, The Cardiovascular Research Institute and The Department of Internal Medicine III, Kurume University School of Medicine, 67 Asahi, Kurume, 830-0011 Japan.
Correspondence to Jeffrey M. Isner, MD, Department of Medicine (Cardiology), St. Elizabeth's Medical Center of Boston, 736 Cambridge St, Boston, MA 02135. E-mail jisner{at}opal.tufts.edu
Abstract—Endothelium-derived
nitric oxide (NO) and its precursor L-arginine have been
implied to promote angiogenesis, but little is known about the precise
mechanism. The inhibition of endogenous NO formation by
N
-nitro-L-arginine methyl
ester (L-NAME) (1 mmol/L) but not its inactive
enantiomer D-NAME (1 mmol/L) inhibited
endothelial cell sprouting from the scratched edge of
the cultured bovine aortic endothelial cell monolayer.
Inhibition of endogenous NO release by L-NAME
was confirmed by amperometric measurement using an NO-specific
electrode. In the modified Boyden chamber, L-NAME (1
mmol/L) significantly inhibited endothelial cell
migration, whereas L-NAME did not affect
endothelial DNA synthesis as assessed by
analysis of [3H]thymidine incorporation. We then
examined alteration of endothelial cell adhesion
molecule expression after the inhibition of NO by L-NAME in
cultured human umbilical vein endothelial cells. In
both normoxic and hypoxic conditions, L-NAME (1
mmol/L) inhibited surface expression of integrin 
vß3, which is an
important integrin facilitating endothelial cell
survival and angiogenesis. However, L-NAME did not affect
the expression of platelet endothelial cell
adhesion molecule-1, intercellular adhesion molecule-1, vascular
endothelial adhesion molecule-1, gap junction protein
connexin 43, and VE-cadherin, which have been reported to potentially
affect angiogenesis. In summary, inhibition of
endothelial NO synthase by L-NAME
attenuated endothelial cell migration but not
proliferation in vitro. Furthermore, endogenous
endothelium-derived NO maintains the functional
expression of integrin vß3, a mediator for
endothelial migration, survival, and angiogenesis.
Endothelium-derived NO, thus, may play an important
role in mediating angiogenesis by supporting
endothelial cell migration, at least partly, via an
integrin-dependent mechanism.
Key Words: angiogenesis • endothelium-derived relaxing factor • cell adhesion molecule • endothelial migration
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