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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2284.)
© 2004 American Heart Association, Inc.

Vascular Biology

Essential Role of Vascular Endothelial Growth Factor and Flt-1 Signals in Neointimal Formation After Periadventitial Injury

Qingwei Zhao; Kensuke Egashira; Ken-ichi Hiasa; Minako Ishibashi; Shujiro Inoue; Kisho Ohtani; Chunyan Tan; Masabumi Shibuya; Akira Takeshita; Kenji Sunagawa

From the Department of Cardiovascular Medicine (Q.Z., K.E., K.H., M.I., S.I., K.O., C.T., A.T., K.S.), 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

Objective— Vascular endothelial growth factor (VEGF) is upregulated after arterial injury. Its role in the pathogenesis of neointimal formation after periadventitial injury, however, has not been addressed.

Methods and Results— Expression of VEGF and its receptors but not that of placental growth factor markedly increased with the development of neointimal formation in hypercholesterolemic mice after cuff-induced periarterial injury. Transfection with the murine soluble Flt-1 (sFlt-1) gene to block VEGF in vivo in mice inhibited early inflammation and later neointimal formation. The sFlt-1 gene transfer did not affect plasma lipid levels but attenuated increased expression of VEGF, Flt-1, Flk-1, monocyte chemoattractant protein-1, and other inflammation-promoting factors. Mice with Flt-1 kinase deficiency also displayed reduced neointimal formation.

Conclusions— Inflammatory changes mediated by VEGF and Flt-1 signals play an important role in the pathogenesis of neointimal formation after cuff-induced periadventitial injury. VEGF might promote neointimal formation by acting as a proinflammatory cytokine.

We examined the role of vascular endothelial growth factor (VEGF) in the pathogenesis of neointimal formation after cuff-induced periadventitial injury in mice. Blockade of VEGF by transfecting mice with the sFlt-1 gene inhibited neointimal formation associated with reduced expression of various inflammation-promoting factors. Therefore, VEGF might promote neointimal formation by acting as a proinflammatory cytokine after cuff-induced periadventitial injury.

Key Words: remodeling • growth substances • inflammation • arteriosclerosis • gene therapy

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