Ho. Akman et al., Response to hypoxia involves transforming growth factor-beta 2 and Smad proteins in human endothelial cells, BLOOD, 98(12), 2001, pp. 3324-3331
Oxygen deprivation (hypoxia) is a consistent component of ischemia that ind
uces an inflammatory and prothrombotic response in the endothelium. In this
report, it is demonstrated that exposure of endothelial cells to hypoxia (
1% O-2) increases messenger RNA and protein levels of transforming growth f
actor-beta2 (TGF-beta2), a cytokine with potent regulatory effects on vascu
lar inflammatory responses. Messenger RNA levels of the TGF-beta2 type II m
embrane receptor, which is a serine threonine kinase, also increased. The s
timulatory effect of hypoxia was found to occur at the level of transcripti
on of the TGF-beta2 gene and involves Smad proteins, a class of intracellul
ar signaling proteins that mediates the downstream effects of TGF-beta rece
ptors. Transient transfection studies showed that the region spanning -77 a
nd -40 base pairs within the TGF-beta2 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-<beta>. In addition,
specific binding to a Smad-binding oligonucleotide was observed with nucle
ar extracts from hypoxic endothelial cells but not from nonhypoxic cells. I
t 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. (Blood. 2001;98:3324-3331) (C)
2001 by The American Society of Hematology.