Transfection of the DNA for the receptor KDR/flk-1 attenuates neointimal proliferation and luminal narrowing in a coronary stent angioplasty model

Abstract

Background. 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 reendothelialization 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. Methods. In a minipig model, we performed coronary stent implantation, followed by injection of either KDR/flk-1 DNA (200 mu g 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. Results. 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. Conclusion. 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. (c) 2006 Elsevier Inc. All rights reserved.