Published online before print October 3, 2002, doi: 10.1161/01.RES.0000040397.23817.E5
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Submitted on March 13, 2002
Revised on September 19, 2002
Accepted on September 20, 2002
Smad2 Mediates Transforming Growth Factor-ß Induction of Endothelial Nitric Oxide Synthase Expression
Marta Saura ;
From the Department of Physiology (M.S., M.R.-P.), Universidad de Alcalá, Madrid, Spain; Unidad de Nefrología (D.R.-P.), Hospital Universitario "Principe de Asturias," Madrid, Spain; Fundacion Centro Nacional de Investigaciones Cardiovasculares (CNIC) (C.Z.), Madrid, Spain; and the Division of Cardiology, Department of Medicine (W.C., C.B., C.J.L.), The Johns Hopkins University School of Medicine, Baltimore, Md.
* To whom correspondence should be addressed. E-mail: clowenst{at}jhmi.edu.
Transforming growth factor-ß (TGF-ß) increases expression of endothelial nitric oxide synthase (eNOS), although the precise mechanism by which it does so is unclear. We report that Smad2, a transcription factor activated by TGF-ß, mediates TGF-ß induction of eNOS in endothelial cells. TGF-ß induces Smad2 translocation from cytoplasm to nucleus, where it directly interacts with a specific region of the eNOS promoter. Overexpression of Smad2 increases basal levels of eNOS, and further increases TGF-ß stimulation of eNOS expression. Ectopic expression of Smurf, an antagonizer of Smad2, decreases Smad2 expression and blocks TGF-ß induction of eNOS. Because Smad2 can interact with a variety of transcription factors, coactivators, and corepressors, Smad2 may thus act as an integrator of multiple signals in the regulation of eNOS expression.
Key words: endothelial cell • hypoxia • atherosclerosis
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