Effect of siRNA targeting SHP-1 on angiogenesis in hindlimb ischemia

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Vascular endothelial growth factor (VEGF) promotes the growth of vascular endothelial cells and the development of new blood vessels through interaction with VEGF receptor-2 (KDR/flk-1). The binding of VEGF to KDR/flk-1 induces conformational changes in the receptor, followed by dimerization and autophosphorylation of the tyrosine residues. The phosphorylated KDR/flk-1 can be a substrate for intracellular protein tyrosine phosphatases. SHP-1 , a cytoplasmic protein tyrosine phosphatase that contain two Src homology 2 domains in its N-terminal half, interacts with activated cytokine, growth factor, and antigen receptors and plays a negative regulatory role in signal transduction pathways by dephosphorylation of the receptors or receptor substrates to which it binds. Thus, therapeutic angiogenesis designed to inhibit expression of SHP-1 would be beneficial in hindlimb ischemia. Here we report that siRNA targeting SHP-1 activates KDR/flk-1 and accelerates angiogenesis in a rat model of hindlimb ischemia. Upon injection to the ischemic adductor muscle, vector-based siRNA reduced SHP-1, increased phosphorylation of KDR/flk-1, and markedly increased capillary density. Our data demonstrate in vivo the potential use of siRNA targeting SHP-1 as therapy for peripheral ischemic diseases.