Soluble flt-1 gene transfer ameliorates neointima formation after wire injury in flt-1 tyrosine kinase-deficient mice

Jun Ichiro Koga, Tetsuya Matoba, Kensuke Egashira, Mitsuki Kubo, Miho Miyagawa, Eiko Iwata, Katsuo Sueishi, Masabumi Shibuya, Kenji Sunagawa

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

OBJECTIVE: We have demonstrated that vascular endothelial growth factor (VEGF) expression is upregulated in injured vascular wall, and blockade of VEGF inhibited monocyte infiltration and neointima formation in several animal models. In the present study, we aimed to clarify relative role of two VEGF receptors, flt-1 versus flk-1/KDR, in neointima formation after injury using flt-1 tyrosine kinase-deficient (Flt-1 TK) mice and soluble Flt-1(sFlt-1) gene transfer. METHODS AND RESULTS: Neointima formation was comparable between wild-type and Flt-1 TK mice 28 days after intraluminal wire injury in femoral arteries. By contrast, neointima formation was significantly suppressed by sFlt-1 gene transfer into Flt-1 TK mice that blocks VEGF action on flk-1 (intima/media ratio: 2.8±0.4 versus 1.4±0.4, P<0.05). The inhibition of neointima formation was preceded by significant reduction of monocyte chemoattractant protein (MCP-1) expression in vascular smooth muscle cells (VSMCs) and monocyte infiltration 7 days after injury. Gene transfer of sFlt-1 or treatment of flk-1-specific antibody significantly inhibited VEGF-induced MCP-1 expression determined by RT-PCR in cultured aortic tissue and VSMCs. MCP-1-induced chemotaxis was equivalent between wild-type and Flt-1 TK mice. CONCLUSIONS: These results suggest that endogenous VEGF accelerates neointima formation through flk-1 by regulating MCP-1 expression in VSMCs and macrophage-mediated inflammation in injured vascular wall in murine model of wire injury.

Original languageEnglish
Pages (from-to)458-464
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume29
Issue number4
DOIs
Publication statusPublished - Apr 1 2009

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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