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(Circulation Research. 2003;92:314.)
© 2003 American Heart Association, Inc.

Integrative Physiology

Conditional Expression of a Dominant-Negative c-Myb in Vascular Smooth Muscle Cells Inhibits Arterial Remodeling After Injury

Xiao-Mang You^*, Imran N. Mungrue^*, Waseem Kalair, Talat Afroze, Bheeshma Ravi, Al Muktafi Sadi, Robert Gros, Mansoor Husain

From the Division of Cellular and Molecular Biology (X.-M.Y., W.K., T.A., B.R., A.M.S., R.G., M.H.), The Toronto General Hospital Research Institute; Heart and Stroke Richard Lewar Centre of Excellence (I.N.M., R.G., M.H.) and the Departments of Medicine, and Laboratory Medicine and Pathobiology (I.N.M., M.H.), University of Toronto, Ontario, Canada.

Correspondence to Mansoor Husain, The Toronto General Hospital, EN-12-221, 200 Elizabeth St, Toronto ON, M5G 2C4. E-mail mansoor.husain{at}utoronto.ca

Inhibiting activity of the c-Myb transcription factor attenuates G₁ to S phase cell cycle transitions in vascular smooth muscle cells (SMCs) in vitro. To determine the effects of arterial SMC-specific expression of a dominant-negative c-Myb molecule (Myb-Engrailed) on vascular remodeling in vivo, we performed carotid artery wire-denudation in 2 independent lines of binary transgenic mice with SM22 promoter-defined Doxycycline-suppressible expression of Myb-Engrailed. Adult mice with arterial SMC-specific expression of Myb-Engrailed were overtly normal in appearance and did not display any changes in cardiovascular structure or physiology. However, bromodeoxyuridine-defined arterial SMC proliferation, neointima formation, medial hyperplasia, and arterial remodeling were markedly decreased in mice expressing arterial SMC-restricted Myb-Engrailed after arterial injury. These data suggest that c-Myb activity in arterial SMCs is not essential for arterial structure or function during development, but is involved in the proliferation of arterial SMCs as occurs in vascular pathology, and that the expression of a dominant-negative c-Myb can dramatically reduce adverse arterial remodeling in an in vivo model of restenosis. As such, this model represents a novel tissue-specific strategy for the potential gene therapy of diseases characterized by arterial SMC proliferation.

Key Words: dominant-negative c-Myb • conditional transgenic mouse • SM22 • restenosis • vascular smooth muscle cell proliferation

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