Published online before print January 16, 2003, doi: 10.1161/01.RES.0000056758.73215.5A
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Submitted on September 27, 2002
Revised on December 20, 2002
Accepted on January 7, 2003
Conditional Expression of a Dominant-Negative c-Myb in Vascular Smooth Muscle Cells Inhibits Arterial Remodeling After Injury
Xiao-Mang You ;
From the Division of Cellular and Molecular Biology (X.-M.Y., W.K., T.A., B.R., 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.
* To whom correspondence should be addressed. 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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