© 1997 American Heart Association, Inc.
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Induction of Vascular Endothelial Growth Factor in Balloon-Injured Baboon Arteries
A Novel Role for Reactive Oxygen Species in Atherosclerosis
From the Division of Cardiology (J.R., Z.Y.H., L.-Y.Y., Y.W., G.N.R., M.S.R., C.P.), University of Texas Medical Branch at Galveston, and the Division of Hematology and Oncology (S.R.H., L.A.H.), Department of Medicine, and the Yerkes Regional Primate Research Institute (A.B.K.), Emory University School of Medicine, Atlanta, Ga.
Correspondence to Dr Cam Patterson, Division of Cardiology, 301 University Blvd, 9.138 Medical Research Building, Galveston, TX 77555-1064. E-mail camp{at}cardiology.utmb.edu
Abstract Neovascularization is a hallmark of neointimal formation in atherosclerotic plaques and restenotic lesions. Vascular endothelial growth factor (VEGF) promotes neovascular growth, whereas oxidative stress is a potent factor in vascular cell proliferation. To investigate the mechanisms of neovascular formation, we treated human and rat vascular smooth muscle cells (VSMCs) with H2O2. Northern blot analysis demonstrated a dose- and time-dependent increase in VEGF mRNA, with a maximum of 4-fold at 3 hours (200 µmol/L). As determined by immunoblotting and enzyme-linked immunosorbent assay, VEGF protein expression and secretion were similarly increased. Human umbilical vein endothelial cells were treated with conditioned medium from VSMCs incubated with 200 µmol/L H2O2. DNA synthesis, measured by thymidine incorporation, was increased 4-fold compared with control, an effect that was blocked by a neutralizing anti-VEGF antibody. The lipid peroxidation product 4-hydroxynonenal (1 µmol/L), an endogenous reactive oxygen species present in human atherosclerotic lesions, also increased VEGF secretion in VSMCs in a similar time-dependent fashion. Immunohistochemical staining and in situ hybridization of aortic sections from balloon-injured baboons demonstrated increased VEGF expression in discrete areas of the neointima and media compared with control sections, and expression correlated with the generation of 4-hydroxynonenal. Regulators of VEGF expression, such as reactive oxygen species, may enhance neovascularization of atherosclerotic and restenotic arteries.
Key Words: angiogenesis • gene regulation • oxidative stress • atherosclerosis • proliferation
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