This Article Full Text Full Text (PDF) All Versions of this Article: 110/16/2430    most recent 01.CIR.0000145120.37891.8Av1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hutter, R. Articles by Sauter, B. V. Search for Related Content PubMed PubMed Citation Articles by Hutter, R. Articles by Sauter, B. V. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Medline Plus Health Information Genes and Gene Therapy Related Collections Restenosis Restenosis Other Vascular biology Angiogenesis Related Article

(Circulation. 2004;110:2430-2435.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Vascular Endothelial Growth Factor Regulates Reendothelialization and Neointima Formation in a Mouse Model of Arterial Injury

Randolph Hutter, MD^*; Francine E. Carrick, PhD^*; Carolina Valdiviezo, MD; Claire Wolinsky, BS; John S. Rudge, PhD; Stanley J. Wiegand, PhD; Valentin Fuster, MD, PhD; Juan J. Badimon, PhD; Bernhard V. Sauter, MD

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.

Correspondence to Bernhard Sauter, MD, Division of Gastroenterology, Box 1069, Mount Sinai School of Medicine, 1425 Madison Ave, New York, NY 10029. E-mail bernhard.sauter{at}mssm.edu

Received April 13, 2004; revision received June 1, 2004; accepted June 25, 2004.

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.

Key Words: angiogenesis • endothelium • gene therapy • stenosis

Related Article:

The Role of Vascular Endothelial Growth Factor in Restenosis: The Controversy Continues

Ichiro Shiojima and Kenneth Walsh
Circulation 2004 110: 2283-2286. [Full Text]

This article has been cited by other articles:

				B. H. Walpoth, P. Zammaretti, M. Cikirikcioglu, E. Khabiri, M. K. Djebaili, J.-C. Pache, J.-C. Tille, Y. Aggoun, D. Morel, A. Kalangos, et al. Enhanced intimal thickening of expanded polytetrafluoroethylene grafts coated with fibrin or fibrin-releasing vascular endothelial growth factor in the pig carotid artery interposition model J. Thorac. Cardiovasc. Surg., May 1, 2007; 133(5): 1163 - 1170. [Abstract] [Full Text] [PDF]

				J. Cheng, R. Cui, C.-H. Chen, and J. Du Oxidized Low-Density Lipoprotein Stimulates p53-Dependent Activation of Proapoptotic Bax Leading to Apoptosis of Differentiated Endothelial Progenitor Cells Endocrinology, May 1, 2007; 148(5): 2085 - 2094. [Abstract] [Full Text] [PDF]

				A. N. Cheema, T. Hong, N. Nili, A. Segev, J. G. Moffat, K. E. Lipson, A. R. Howlett, D. W. Holdsworth, M. J. Cole, B. Qiang, et al. Adventitial Microvessel Formation After Coronary Stenting and the Effects of SU11218, a Tyrosine Kinase Inhibitor J. Am. Coll. Cardiol., March 7, 2006; 47(5): 1067 - 1075. [Abstract] [Full Text] [PDF]

				V. Eremina, S. Cui, H. Gerber, N. Ferrara, J. Haigh, A. Nagy, M. Ema, J. Rossant, S. Jothy, J. H. Miner, et al. Vascular Endothelial Growth Factor A Signaling in the Podocyte-Endothelial Compartment Is Required for Mesangial Cell Migration and Survival J. Am. Soc. Nephrol., March 1, 2006; 17(3): 724 - 735. [Abstract] [Full Text] [PDF]

				H. Tan, X. Jiang, F. Yang, Z. Li, D. Liao, J. Trial, M. J. Magera, W. Durante, X. Yang, and H. Wang Hyperhomocysteinemia inhibits post-injury reendothelialization in mice Cardiovasc Res, January 1, 2006; 69(1): 253 - 262. [Abstract] [Full Text] [PDF]

				J. Dulak, S. P Schwarzacher, R. H Zwick, H. Alber, G. Millonig, C. Weiss, H. Hugel, M. Frick, A. Jozkowicz, O. Pachinger, et al. Effects of local gene transfer of VEGF on neointima formation after balloon injury in hypercholesterolemic rabbits Vascular Medicine, November 1, 2005; 10(4): 285 - 291. [Abstract] [PDF]

				R. Khurana, M. Simons, J. F. Martin, and I. C. Zachary Role of Angiogenesis in Cardiovascular Disease: A Critical Appraisal Circulation, September 20, 2005; 112(12): 1813 - 1824. [Abstract] [Full Text] [PDF]

				I. Shiojima and K. Walsh The Role of Vascular Endothelial Growth Factor in Restenosis: The Controversy Continues Circulation, October 19, 2004; 110(16): 2283 - 2286. [Full Text] [PDF]