on October 11, 2004
Published online before print October 11, 2004, doi: 10.1161/01.CIR.0000145120.37891.8A
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Submitted on April 13, 2004
From the Division of Gastroenterology and Carl C. Icahn Institute for Gene Therapy and Molecular Medicine (F.E.C., B.V.S), and the Zena and Michael A. Wiener Cardiovascular Institute (R.H., C.V., C.W., V.F., J.J.B.), Mount Sinai School of Medicine, New York, NY, and Regeneron Pharmaceuticals Inc (J.S.R., S.J.W.), Tarrytown. * To whom correspondence should be addressed. E-mail: bernhard.sauter{at}mssm.edu.
Background--The rate of reendothelialization is critical in neointima formation after arterial injury. Vascular endothelial growth factor (VEGF), a potent endothelial mitogen, has been advocated for accelerating endothelial repair and preventing intimal hyperplasia after percutaneous coronary interventions. However, the precise mechanism of action of VEGF treatment and the physiologic role of endogenous VEGF after arterial injury are not well described. To better understand the role of VEGF in arterial repair, we overexpressed both VEGF and a soluble, chimeric VEGF receptor (VEGF-trap), which binds free VEGF with high affinity, in a mouse model of arterial injury. Methods and Results--Four groups of C57BL/6 mice underwent denuding endothelial injury 1 day after systemic injection of recombinant adenovirus expressing (1) VEGF, (2) VEGF-trap, (3) VEGF plus VEGF-trap, or (4) control adenovirus. Circulating levels of adenovirus-encoded proteins were significantly elevated after gene transfer. VEGF overexpression accelerated reendothelialization and increased luminal endothelial cell proliferation 2 weeks after arterial injury (P<0.05), resulting in decreased neointima formation at 4 weeks compared with control (P<0.01). Cotreatment with VEGF-trap completely sequestered free VEGF and abrogated the beneficial effect of VEGF overexpression. Interestingly, sequestration of endogenous VEGF by VEGF-trap overexpression alone also led to delayed reendothelialization at 2 weeks (P<0.01) and increased neointima formation at 4 weeks (P<0.01). Conclusions--VEGF overexpression accelerated endothelial repair and inhibited neointima formation after arterial injury. Conversely, sequestration of exogenous and/or endogenous VEGF by VEGF-trap delayed reendothelialization and significantly increased neointima size. This demonstrates the therapeutic potential of VEGF but also emphasizes the important physiologic role of endogenous VEGF in vascular repair.
Revised on June 1, 2004
Accepted on June 25, 2004
Vascular Endothelial Growth Factor Regulates Reendothelialization and Neointima Formation in a Mouse Model of Arterial Injury
Randolph Hutter MD,
Key words: angiogenesis • endothelium • gene therapy • stenosis
Related Article:
Circulation 2004 110: 2283-2286.
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