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(Circulation. 2005;111:1071-1077.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Rad GTPase Attenuates Vascular Lesion Formation by Inhibition of Vascular Smooth Muscle Cell Migration

Mingui Fu, MD, PhD^*; Jifeng Zhang, MS^*; Yu-Hua Tseng, PhD; Taixing Cui, MD, PhD; Xiaojun Zhu, MD; Yan Xiao, MD; Yongshan Mou, MD; Hector De Leon, MD, PhD; Mary M.J. Chang, PhD; Yasuo Hamamori, MD, PhD; C. Ronald Kahn, MD; Yuqing E. Chen, MD, PhD

From the Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Ga (M.F., J.Z., T.C., Y.X., Y.M., H.D.L., Y.E.C.); Research Division, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Mass (Y.-H.T., C.R.K.); Cardiovascular Research Institute, Peking University Health Science Center, Beijing, China (X.Z.); Center for Comparative Respiratory Biology and Medicine, School of Medicine, University of California, Davis (M.M.J.C.); and Center for Cardiovascular Development, Department of Medicine, Baylor College of Medicine, Houston, Tex (Y.H.). Dr Fu is now at the Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas.

Correspondence to Dr Y.E. Chen, Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Dr SW, Atlanta, GA 30310. E-mail echen{at}msm.edu

Received July 13, 2004; revision received October 3, 2004; accepted November 2, 2004.

Background— Rad (Ras associated with diabetes) GTPase is a prototypic member of a new subfamily of Ras-related GTPases with unique structural features, although its physiological role remains largely unknown. In the present study, we characterized the Rad function in vascular smooth muscle cells (VSMCs) and the influence of adenovirus-mediated Rad (Ad-Rad) gene delivery on vascular remodeling after experimental angioplasty.

Methods and Results— We documented for the first time that neointimal formation using balloon-injured rat carotid arteries was associated with a significant increase in Rad expression as determined by immunohistochemistry and quantitative real-time reverse-transcriptase polymerase chain reaction. The levels of Rad expression in VSMCs were highly induced by platelet-derived growth factor and tumor necrosis factor-. Morphometric analyses 14 days after injury revealed significantly diminished neointimal formation in the Ad-Rad–treated carotid arteries compared with Ad-GFP or PBS controls, whereas the mutated form of Rad GTPase, which can bind GDP but not GTP, increased neointimal formation. Overexpression of Rad significantly inhibited the attachment and migration of VSMCs. In addition, Rad expression dramatically reduced the formation of focal contacts and stress fibers in VSMCs by blocking the Rho/ROK signaling pathway.

Conclusions— Our data clearly identified Rad GTPase as a novel and critical mediator that inhibits vascular lesion formation. Manipulation of the Rad signaling pathway may provide new therapeutic approaches that will limit vascular pathological remodeling.

Key Words: atherosclerosis • cell movement • cells, vascular smooth muscle • monomeric GTP-binding proteins • restenosis

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