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Activation of Hypoxia‐Inducible Factor‐1 by Sphingosine‐1‐Phosphate in vascular cells
Author(s) -
Michaud Dumont Maude,
Gratton JeanPhilippe,
Richard Darren
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.637.1
Subject(s) - sphingosine 1 phosphate , angiogenesis , microbiology and biotechnology , hypoxia inducible factor 1 , inducer , activator (genetics) , cellular adaptation , sphingosine , hypoxia (environmental) , hypoxia inducible factors , vascular smooth muscle , biology , transcription factor , chemistry , receptor , cancer research , biochemistry , gene , endocrinology , oxygen , smooth muscle , organic chemistry
Sphingosine‐1‐phosphate(S1P) is a bioactive phospholipid playing a key role in angiogenesis by promoting a variety of vascular cell events. Hypoxia‐inducible factor‐1(HIF‐1), a transcriptional activator of many genes essential for adaptation to lowered oxygen levels, is also a major angiogenic inducer. Interestingly, S1P and HIF‐1 are both implicated in different cardiovascular diseases and in tumor progression. Recent studies have shown that non‐hypoxic stimuli can activate HIF‐1 in oxygenated conditions. Here, we attempt to determine whether S1P can modulate the vascular activation of HIF‐1. We show that treatment of cultured vascular cells with S1P strongly increases HIF‐1α but not HIF‐2α protein levels, through VHL‐independent stabilization of HIF‐1α. Using pharmacological inhibitors we show that elevation of HIF‐1α expression occurs through the S1P2 receptor. We demonstrate, that the HIF‐1 nuclear dimer formed upon S1P stimulation, is transcriptionally active and specifically binds to hypoxia‐responsive elements. Moreover, in smooth muscle cells, S1P regulates genes via HIF‐1, since the transcripts are diminished when HIF‐1α is silenced. Our results therefore identify S1P as a potent inducer of HIF‐1. We believe that the discovery of novel activators of HIF‐1, such as S1P, and comprehension of subsequent downstream events will have a strong impact on different aspects of vascular biology. This work is supported by the Canadian Institutes of Health Research