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Prepublished online as a Blood First Edition Paper on October 31, 2002; DOI 10.1182/blood-2002-02-0629.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2253-2260
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Cellular response to hypoxia involves signaling via Smad
proteins
Hong Zhang,
Hasan O. Akman,
Eric L. P. Smith,
Jin Zhao,
Joanne E. Murphy-Ullrich M. A. Q. Siddiqui, and
Olcay A. Batuman
From the Department of Anatomy and Cell
Biology, the Division of Hematology/Oncology, the Department of
Medicine, the Center for Cardiovascular and Molecular Medicine, and the
Department of Psychiatry, State University of New York Downstate
Medical Center, Brooklyn, NY; and the Department of Pathology, The Cell
Adhesion and Matrix Research Center, University of Alabama at
Birmingham, Birmingham, AL.
The transforming growth factor- (TGF-) family of cytokines
regulates vascular development and inflammatory responses. We have
recently shown that exposure of human umbilical vein endothelial cells
(HUVECs) to hypoxia (1% O2) increases gene expression and bioactivation of TGF-2 and induces its downstream effectors, Smad
proteins (Smads), to associate with DNA. In the present study, we show
that hypoxia-induced TGF-2 gene expression is dependent on
thrombospondin-1-mediated bioactivation of latent TGF-. Blocking TGF-2 but not TGF-1 in hypoxic endothelial cell cultures
inhibited induction of the TGF-2 gene, indicating that an autocrine
mechanism driven by bioactivation of TGF-2 leads to its gene
expression in hypoxic HUVECs. Exposure of HUVECs to hypoxia resulted in
phosphorylation and nuclear transportation of Smad2 and Smad3 proteins
as well as stimulation of transcriptional activities of Smad3 and the transcription factor hypoxia-inducible factor-1 and culminated in
up-regulation of TGF-2 gene expression. Autocrine regulation of
TGF-2 production in hypoxia may involve cross-talk between Smad3 and
HIF-1 signaling pathways, and could be an important mechanism by
which endothelial cells respond to hypoxic stress.
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