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Targeting v3 and 51 for gene delivery to proliferating VSMCs: synergistic effect of TGF-1

Departments of ¹Cardiology and ²Clinical Sciences, Institute of Liver Studies, King's College London, London SE5 9PJ; and ³Cardiovascular Research Group, School of Animal and Microbial Sciences, The University of Reading, Reading, Berkshire RG6 6AJ, United Kingdom

Submitted 3 February 2003 ; accepted in final form 30 April 2003

TGF-1 levels increase after vascular injury and promote vascular smooth muscle cell (VSMC) proliferation. We define a nonviral gene delivery system that targets v3 and 51 integrins that are expressed on proliferating VSMCs and strongly induced by TGF-1. A 15-amino acid RGDNP-containing peptide from American Pit Viper venom was linked to a Lys(16) peptide as vector (molossin vector) and complexed with Lipofectamine or fusogenic peptide for delivery of luciferase or -galactosidase reporter genes to primary cultures of human, rabbit, and rat VSMCs. Preincubation of VSMCs with TGF-1 for 24 h, but not with PDGF-BB, interferon-, TNF-, nor PMA, increased v3 and 51 expressions on VSMCs and enhanced gene delivery of molossin vector. Thus -galactosidase activity increased from 35 ± 5% (controls) to 75 ± 5% after TGF-1 treatment, and luciferase activity increased fourfold over control values. Potential use of this system in vessel bypass surgery was examined in an ex vivo rat aortic organ culture model after endothelial damage. Molossin vector system delivered -galactosidase to VSMCs in the vessel wall that remained for up to 12 days posttransfection. The molossin vector system, when combined with TGF-1, enhances gene delivery to proliferating VSMCs and might have clinical applications for certain vasculoproliferative diseases.

integrin; peptide vector; molossin rector