Intramuscular Gene Transfer of Soluble Tumor Necrosis Factor-α Receptor 1 Activates Vascular Endothelial Growth Factor Receptor and Accelerates Angiogenesis in a Rat Model of Hindlimb Ischemia

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Abstract
Background— In a pathological setting, tumor necrosis factor (TNF)-α inhibits the proliferative response of endothelial cells through inactivation of receptors for vascular endothelial growth factor (VEGF). Soluble TNF-α receptor 1 (sTNFR1) is an extracellular domain of TNFR1 and an antagonist to TNF-α. In the present study, we examined the effect of sTNFR1 expression plasmid on receptor for VEGF (KDR/flk-1) and angiogenesis in a rat model of hindlimb ischemia. Methods and Results— The left femoral artery was exposed and excised to induce limb ischemia. A total of 400 μg of sTNFR1 or LacZ plasmid was injected into 3 different sites of the adductor muscle immediately after the induction of ischemia. TNF-α bioactivity in ischemic adductors increased in rats receiving LacZ plasmid compared with sham-operated rats. However, sTNFR1 plasmid significantly suppressed the increase in TNF-α bioactivity. KDR/flk-1 mRNA and tyrosine phosphorylation of KDR/flk-1 were significantly increased in the muscles injected with sTNFR1 plasmid compared with those injected with LacZ plasmid. VEGF increased both in muscles injected with sTNFR1 plasmid and in muscles injected with LacZ plasmid but did not differ significantly between them. At 21 days after the induction of ischemia, the sTNFR1 plasmid-transfected muscles showed significantly increased capillary density compared with LacZ plasmid-transfected muscles. Conclusions— In a rat model of hindlimb ischemia, VEGF increased but activation of KDR/flk-1 was suppressed, possibly by TNF-α, which might impair angiogenesis. Suppression of TNF-α with sTNFR1 plasmid upregulated KDR/flk-1 and accelerated angiogenesis. Local transfection of the sTNFR1 gene can be a new strategy for therapeutic angiogenesis in peripheral ischemic diseases.

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