Transfection of the DNA for the Receptor KDR/flk-1 Attenuates Neointimal Proliferation and Luminal Narrowing in a Coronary Stent Angioplasty Model

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Neointimal proliferation resulting in luminal renarrowing is the major cause of restenosis limiting the long-term success of coronary angioplasty in 20 to 30% of patients. Local transfection of the DNA encoding for VEGF has been shown to enhance re-endothelialization and reduce neointimal proliferation in an experimental model. We tested the hypothesis that transfection of the DNA for the receptor of vascular endothelial growth factor VEGF, KDR-flk-1, reduces neointimal proliferation after angioplasty. In a minipig model, we performed coronary stent implantation, followed by injection of either KDR/flk-1 DNA (200 microg of linearized DNA in a CMV-promotor) or LacZ control in two coronary artery segments per animal in a randomized, blinded protocol (n = 22 animals). Expression of KDR/flk-1 was analyzed using in situ hybridization after 4, 7, and 14 days. In KDR-transfected coronary segments, expression of KDR/flk-1 occurred earlier and to much stronger extent compared to LacZ-transfected segments. After 4 weeks (n = 10) neointimal proliferation and luminal narrowing was significantly reduced in KDR/flk-1 transfected animals. No expression of locally transfected DNA was detected in other organs. The hypothesis is supported, that expression of the VEGF-receptor KDR/flk-1 can be rate-limiting for endothelial regeneration and that its transient overexpression at the time angioplasty can prevent excessive neointimal proliferation resulting in restenosis.