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

• Published in: The Journal of surgical research 2006-11, Vol.136 (1), p.120-124
• Main Authors: Buchwald, Arnd B., Kunze, Christopher, Waltenberger, Johannes, Unterberg-Buchwald, Christina
• Format: Article
• Language: English
• Subjects: Angioplasty, Balloon, Coronary; Animals; Cell Division; coronary angioplasty; Coronary Restenosis - pathology; Coronary Restenosis - prevention & control; DNA - pharmacokinetics; DNA transfer; Genetic Therapy - methods; In Situ Hybridization; Lac Operon; restenosis; RNA, Messenger - metabolism; Stents; Swine; Swine, Miniature; Transfection; Tunica Intima - pathology; vascular endothelial growth factor receptor KDR/flk-1; Vascular Endothelial Growth Factor Receptor-2 - genetics
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2006.06.011

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 μg 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.