Soluble Flt-1 Gene Transfer Ameliorates Neointima Formation After Wire Injury in flt-1 Tyrosine Kinase–Deficient Mice

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 Ϫ/Ϫ ) mice and soluble Flt-1(sFlt-1) gene transfer. Methods and Results-Neointima formation was comparable between wild-type and Flt-1 TK Ϫ/Ϫ 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 Ϫ/Ϫ mice that blocks VEGF action on flk-1 (intima/media ratio: 2.8Ϯ0.4 versus 1.4Ϯ0.4, PϽ0.05). 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 Ϫ/Ϫ mice. Conclusions-These

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Vasa Vasorum in Normal and Diseased Arteries

“…Conversely, inhibition of growth factor signaling reduced it. [78][79][80] Microcomputed tomography imaging further demonstrates a direct correlation between the computed tomography-determined extent of adventitial angiogenesis and the extent of neointima. 19,81 Thus, there is a strong correlation between the extent of the adventitial vasculature and the extent of neointima formation.…”

Evaluation of Vascular Endothelial Growth Factor and Its Receptors in Human Neointima

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