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(Circulation Research. 2009;104:380.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Heparanase Alters Arterial Structure, Mechanics, and Repair Following Endovascular Stenting in Mice

Aaron B. Baker, Adam Groothuis, Michael Jonas, David S. Ettenson, Tarek Shazly, Eyal Zcharia, Israel Vlodavsky, Philip Seifert, Elazer R. Edelman

From the Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology (A.B.B., A.G., M.J., D.S.E., T.S., P.S., E.R.E.), Massachusetts Institute of Technology, Cambridge; Cardiovascular Division (M.J., E.R.E.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; and Cancer and Vascular Biology Research Center (E.Z., I.V.), Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.

Correspondence to Aaron B. Baker, Massachusetts Institute of Technology, 77 Massachusetts Ave, Building E25, Room 442, Cambridge, MA 02139. E-mail abbaker{at}mit.edu

Heparan sulfate proteoglycans (HSPGs) are potent regulators of vascular remodeling and repair. Heparanase is the major enzyme capable of degrading heparan sulfate in mammalian cells. Here we examined the role of heparanase in controlling arterial structure, mechanics, and remodeling. In vitro studies supported that heparanase expression in endothelial cells serves as a negative regulator of endothelial inhibition of vascular smooth muscle cell (vSMC) proliferation. Arterial structure and remodeling to injury were also modified by heparanase expression. Transgenic mice overexpressing heparanase had increased arterial thickness, cellular density, and mechanical compliance. Endovascular stenting studies in Zucker rats demonstrated increased heparanase expression in the neointima of obese, hyperlipidemic rats in comparison to lean rats. The extent of heparanase expression within the neointima strongly correlated with the neointimal thickness following injury. To test the effects of heparanase overexpression on arterial repair, we developed a novel murine model of stent injury using small diameter self-expanding stents. Using this model, we found that increased neointimal formation and macrophage recruitment occurs in transgenic mice overexpressing heparanase. Taken together, these results support a role for heparanase in the regulation of arterial structure, mechanics, and repair.

Key Words: heparanase • vascular remodeling • restenosis • stenting • arterial compliance

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