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Blood, 1 December 2001, Vol. 98, No. 12, pp. 3324-3331
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Response to hypoxia involves transforming growth factor- 2 and
Smad proteins in human endothelial cells
Hasan O. Akman,
Hong Zhang,
M. A. Q. Siddiqui,
William Solomon,
Eric L. P. Smith, and
Olcay A. Batuman
From the Division of Hematology/Oncology, Department of
Medicine, Center for Cardiovascular and Molecular Medicine, Department
of Psychiatry, State University of New York Downstate Medical Center,
Brooklyn, NY.
Oxygen deprivation (hypoxia) is a consistent component of ischemia
that induces an inflammatory and prothrombotic response in the
endothelium. In this report, it is demonstrated that exposure of endothelial cells to hypoxia (1% O2) increases
messenger RNA and protein levels of transforming growth factor- 2
(TGF-2), a cytokine with potent regulatory effects on vascular
inflammatory responses. Messenger RNA levels of the TGF-2 type II
membrane receptor, which is a serine threonine kinase, also increased. The stimulatory effect of hypoxia was found to occur at the level of
transcription of the TGF-2 gene and involves Smad proteins, a class
of intracellular signaling proteins that mediates the downstream
effects of TGF- receptors. Transient transfection studies showed
that the region spanning  77 and 40 base pairs within the TGF-2
promoter (harboring a Smad-binding "CAGA box") is activated in
hypoxic cells compared with nonhypoxic controls (P < .01). Hypoxia also stimulated transcription from
another promoter, 3TP-Lux, a reporter construct responsive to Smads and TGF-. In addition, specific binding to a Smad-binding
oligonucleotide was observed with nuclear extracts from hypoxic
endothelial cells but not from nonhypoxic cells. It is concluded that
Smad proteins, which can regulate endothelial responses to mechanical
and inflammatory stress, also may play an important role in vascular
responses to hypoxia and ischemia.
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