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(Circulation Research. 2002;91:806.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Smad2 Mediates Transforming Growth Factor-ß Induction of Endothelial Nitric Oxide Synthase Expression

Marta Saura, Carlos Zaragoza, Wangsen Cao, Clare Bao, Manuel Rodríguez-Puyol, Diego Rodríguez-Puyol, Charles J. Lowenstein

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.

Correspondence to Charles Lowenstein, Division of Cardiology, Department of Medicine (W.C., C.B., C.J.L.), The Johns Hopkins University School of Medicine, Baltimore, MD 21205e-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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