Induction of Vascular Endothelial Growth Factor in Balloon-Injured Baboon Arteries: A Novel Role for Reactive Oxygen Species in Atherosclerosis

• Published in: Circulation research 1997-07, Vol.81 (1), p.24-33
• Main Authors: Ruef, Johannes, Hu, Zhao Y, Yin, Li-Yan, Wu, Yaxu, Hanson, Stephen R, Kelly, Andrew B, Harker, Laurence A, Rao, Gadiparthi N, Runge, Marschall S, Patterson, Cam
• Format: Article
• Language: English
• Subjects: Animals; Arteries - injuries; Arteries - metabolism; Arteriosclerosis - etiology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blotting, Northern; Cardiology. Vascular system; Cell Division; Cells, Cultured; Endothelial Growth Factors - genetics; Endothelial Growth Factors - metabolism; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Humans; Hydrogen Peroxide - pharmacology; In Situ Hybridization; Lymphokines - genetics; Lymphokines - metabolism; Male; Medical sciences; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Papio; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - physiology; RNA, Messenger - analysis; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.81.1.24

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 H2 O2. Northern blot analysis demonstrated a dose- and time-dependent increase in VEGF mRNA, with a maximum of 4-fold at 3 hours (200 micro mol/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 micro mol/L H2 O2. 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 micro mol/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. (Circ Res. 1997;81:24-33.)