This Article Full Text Full Text (PDF) All Versions of this Article: 107/12/1658    most recent 01.CIR.0000058169.21850.CEv1 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 Badimon, J. J. Search for Related Content PubMed PubMed Citation Articles by Hutter, R. Articles by Badimon, J. J. Related Collections Restenosis Restenosis Angiogenesis Apoptosis Gene therapy Other Vascular biology Other Research

(Circulation. 2003;107:1658.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Decreased Reendothelialization and Increased Neointima Formation With Endostatin Overexpression in a Mouse Model of Arterial Injury

Randolph Hutter, MD^*; Bernhard V. Sauter, MD^*; Ernane D. Reis, MD; Merce Roque, MD; David Vorchheimer, MD; Francine E. Carrick, PhD; John T. Fallon, MD, PhD; Valentin Fuster, MD, PhD; Juan J. Badimon, PhD

From the Zena and Michael A. Wiener Cardiovascular Institute (R.H., E.D.R., M.R., D.V., J.T.F., V.F., J.J.B.), Institute for Gene Therapy and Molecular Medicine (B.V.S., F.E.C.), and Departments of Surgery (E.D.R.) and Pathology (J.T.F.), Mount Sinai School of Medicine, New York, NY.

Correspondence to Bernhard Sauter, MD, Institute for Gene Therapy and Molecular Medicine, Box 1496, Mount Sinai School of Medicine, 1425 Madison Ave, New York, NY 10029. E-mail bernhard.sauter{at}mssm.edu

Background— Impaired endothelial regeneration contributes to arterial lesion formation. Endostatin is a specific inhibitor of endothelial cell growth and induces endothelial cell apoptosis. We examined the effect of endostatin overexpression on reendothelialization and neointima formation in a mouse model of arterial injury.

Methods and Results— Mice underwent femoral arterial denudation and received recombinant adenovirus, expressing either murine endostatin (n=19) or control adenoviral vector (n=12), by jugular vein injection. Endostatin gene transfer resulted in high serum levels of endostatin. Strong adenoviral gene expression of ß-galactosidase–expressing control vector was detected in liver tissue and was absent in the injured arterial wall at 1 week. Deposits of endostatin protein were detected along the denuded arterial wall and were not seen in the noninjured contralateral artery at 1 week. Endostatin deposits were also absent in the injured artery of control vector–treated animals. Overexpression of endostatin led to decreased reendothelialization and increased apoptosis of luminal endothelial cells 2 and 4 weeks after arterial injury (P<0.05). In addition, endostatin overexpression resulted in increased neointima formation (P<0.05). Endothelial apoptosis and neointima area correlated positively with endostatin serum levels, whereas the degree of reendothelialization correlated negatively with endostatin serum levels (P<0.05). Furthermore, poor reendothelialization correlated with increased neointima formation (P<0.05).

Conclusions— In summary, decreased reendothelialization and enhanced endothelial apoptosis, in response to endostatin overexpression, were associated with increased neointima formation. These findings demonstrate that high serum levels of endostatin are capable of inhibiting endothelial regeneration and promoting arterial lesion growth in conditions of endothelial injury.

Key Words: gene therapy • endothelium • apoptosis • arteries • restenosis

This article has been cited by other articles:

				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]

				F. Andreotti and R. C. Becker Atherothrombotic Disorders: New Insights From Hematology Circulation, April 12, 2005; 111(14): 1855 - 1863. [Full Text] [PDF]

				J. F. Arenillas, J. Alvarez-Sabin, J. Montaner, A. Rosell, C. A. Molina, A. Rovira, M. Ribo, E. Sanchez, and M. Quintana Angiogenesis in Symptomatic Intracranial Atherosclerosis: Predominance of the Inhibitor Endostatin Is Related to a Greater Extent and Risk of Recurrence Stroke, January 1, 2005; 36(1): 92 - 97. [Abstract] [Full Text] [PDF]

				R. Hutter, F. E. Carrick, C. Valdiviezo, C. Wolinsky, J. S. Rudge, S. J. Wiegand, V. Fuster, J. J. Badimon, and B. V. Sauter Vascular Endothelial Growth Factor Regulates Reendothelialization and Neointima Formation in a Mouse Model of Arterial Injury Circulation, October 19, 2004; 110(16): 2430 - 2435. [Abstract] [Full Text] [PDF]

				E. Conti, C. Carrozza, E. Capoluongo, M. Volpe, F. Crea, C. Zuppi, and F. Andreotti Insulin-Like Growth Factor-1 as a Vascular Protective Factor Circulation, October 12, 2004; 110(15): 2260 - 2265. [Full Text] [PDF]

				Y.-M. Deng, B. J. Wu, P. K. Witting, and R. Stocker Probucol Protects Against Smooth Muscle Cell Proliferation by Upregulating Heme Oxygenase-1 Circulation, September 28, 2004; 110(13): 1855 - 1860. [Abstract] [Full Text] [PDF]

				E. Ribourtout and J. Raymond Gene Therapy and Endovascular Treatment of Intracranial Aneurysms Stroke, March 1, 2004; 35(3): 786 - 793. [Abstract] [Full Text] [PDF]