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


METHODS
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.


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.


CONCLUSIONS
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.
Buchwald
Arnd B
AB
Städtisches Krankenhaus Kiel, I. Medizinische Klinik, Kiel, Germany. abbuw@aol.com
Kunze
Christopher
C
Waltenberger
Johannes
J
Unterberg-Buchwald
Christina
C
D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D002455:Cell Division; D023903:Coronary Restenosis / Q000473:pathology / Q000517:prevention & control*; D004247:DNA / Q000493:pharmacokinetics; D015316:Genetic Therapy / Q000379:methods*; D017403:In Situ Hybridization; D007763:Lac Operon; D012333:RNA, Messenger / Q000378:metabolism; D015607:Stents; D013552:Swine; D013556:Swine, Miniature; D014162:Transfection; D017539:Tunica Intima / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
D012333:RNA, Messenger; D004247:DNA; D040301:Vascular Endothelial Growth Factor Receptor-2