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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2081.)
© 2005 American Heart Association, Inc.

Vascular Biology

Regulation of Vein Graft Hyperplasia by Survivin, an Inhibitor of Apoptosis Protein

Grace J. Wang; Xin Xin Sui; Hector F. Simosa; Mukesh K. Jain; Dario C. Altieri; Michael S. Conte

From Vascular Surgery Research Laboratory (G.J.W., X.X.S., H.F.S., M.S.C.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; Cardiovascular Division (M.K.J.), Brigham and Women’s Hospital, Boston, Mass; Department of Cancer Biology and the Cancer Center (D.C.A.), University of Massachusetts Medical School, Worcester, Mass.

Correspondence to Michael S. Conte, MD, Division of Vascular Surgery, Brigham and Women’s Hospital. 75 Francis St, Boston, MA 02115. E-mail mconte{at}partners.org

Objective— Survivin (SVV) is an inhibitor of apoptosis protein (IAP) that is upregulated in cancer and has recently been implicated in vascular injury. We sought to investigate the role of SVV in vein graft hyperplasia.

Methods and Results— Adenoviral constructs expressing a dominant-negative (AdT34A) and wild-type (AdWT) SVV were used. Proliferation and apoptosis were assayed on endothelial cells (ECs) and smooth muscle cells (SMCs) from human saphenous vein. A rabbit carotid interposition vein graft model (N=31) was used, with adventitial gene transfer of SVV constructs. In vitro, overexpression of SVV was associated with protection from cytokine-induced apoptosis in ECs and SMCs; conversely, AdT34A directly induced apoptosis in these cells. SMC proliferation was increased by AdWT infection, whereas AdT34A reduced proliferation; both effects were serum-dependent. Expression of platelet-derived growth factor (PDGF) in SMCs was regulated by functional SVV expression in analogous fashion. In vivo, proliferation and apoptosis (7 days), as well as wall thickness (30 days), were modified by adenoviral-mediated SVV expression. Adventitial angiogenesis was regulated by the SVV-expressing constructs in a fashion parallel to wall thickness changes.

Conclusions— SVV is a critical regulator of multiple processes, including proliferation, apoptosis, and angiogenesis, that determine the remodeling response of vein grafts following arterialization.

Vein graft remodeling is incompletely understood. Survivin (SVV) is a unique inhibitor of apoptosis protein that has been implicated in cancer and vascular injury. We investigated the role of SVV in vein graft healing and demonstrate that SVV regulates several processes, including proliferation, apoptosis, and angiogenesis, that determine vein graft remodeling

Key Words: angiogenesis • apoptosis • intimal hyperplasia • proliferation • survivin

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