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(Circulation. 2002;105:1110.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Vascular Endothelial Growth Factor Is Necessary in the Development of Arteriosclerosis by Recruiting/Activating Monocytes in a Rat Model of Long-Term Inhibition of Nitric Oxide Synthesis

Qingwei Zhao, MD; Kensuke Egashira, MD; Shujiro Inoue, MD; Makoto Usui, MD; Shiro Kitamoto, MD; Weihua Ni, MD; Minako Ishibashi, MD; Ken-ichi Hiasa, MD; Toshihiro Ichiki, MD; Masabumi Shibuya, MD; Akira Takeshita, MD

From the Department of Cardiovascular Medicine (Q.Z., K.E., S.I., M.U., S.K., W.N., M.I., K.H., T.I., A.T.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and the Department of Genetics (M.S.), Institute of Medical Science, University of Tokyo, Japan.

Correspondence to Kensuke Egashira, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail egashira{at}cardiol.med.kyushu-u.ac.jp

Background— It remains unclear whether vascular endothelial growth factor (VEGF) is a proarteriosclerotic or an antiarteriosclerotic factor. We recently reported that long-term inhibition of nitric oxide by administering N-nitro-L-arginine methyl ester (L-NAME) induces coronary vascular inflammation and arteriosclerosis.

Methods and Results— We used this animal model to investigate the role of VEGF in arteriosclerosis. We blocked VEGF activity in vivo by transfecting with plasmid DNA encoding the murine soluble FLT-1 (sFLT-1) gene into thigh muscle. Soluble FLT-1 can suppress VEGF activity both by sequestering VEGF and by functioning as a dominant-negative inhibitor of VEGF receptors. We observed vascular inflammation associated with increased VEGF expression within 3 days of L-NAME administration, which was prevented by pretreatment with ACE inhibitor, angiotensin II receptor antagonist, or neutralizing monocyte chemoattractant protein-1 antibody. The sFLT-1 gene transfer attenuated the early vascular inflammation and prevented late arteriosclerosis. The sFLT-1 gene transfer also inhibited increased expression of monocyte chemoattractant protein-1 and transforming growth factor-ß, indicating creation of a positive feedback loop to cause arteriosclerosis.

Conclusions— VEGF is necessary in the development of arteriosclerosis by mediating monocyte recruitment and activation in this model.

Key Words: endothelium-derived factors • remodeling • inflammation • growth substances • gene therapy

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