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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:902.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Sphingosine-1-Phosphate

A Novel Nonhypoxic Activator of Hypoxia-Inducible Factor-1 in Vascular Cells

Maude D. Michaud; Geneviève A. Robitaille; Jean-Philippe Gratton; Darren E. Richard

From the Centre de recherche du CHUQ (M.D.M., G.A.R., D.E.R.), L'Hôtel-Dieu de Québec and the Department of Medicine, Université Laval, Québec, QC, Canada; and the Laboratory of Endothelial Cell Biology (J.-P.G.), Institut de recherches cliniques de Montréal (IRCM), Université de Montréal, QC, Canada.

Correspondence to Darren E. Richard, Centre de Recherche du CHUQ, L'Hôtel-Dieu de Québec, 10 Rue McMahon, Québec, QC G1R 2J6, Canada. E-mail darren.richard{at}crhdq.ulaval.ca

Objective— Sphingosine-1-phosphate (S1P) is a potent bioactive phospholipid responsible for a variety of vascular cell responses. Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator of genes essential for adaptation to low oxygen. S1P and HIF-1 are both important mediators of vascular cell responses such as migation, proliferation, and survival. Studies have shown that nonhypoxic stimuli can activate HIF-1 in oxygenated conditions. Here, we attempt to determine whether S1P can modulate the vascular activation of HIF-1.

Methods and Results— We show that in vascular endothelial and smooth muscle cells, activation of the S1P type-2 receptor by S1P strongly increases HIF-1 protein levels, the active subunit of HIF-1. This is achieved through pVHL-independent stabilization of HIF-1. We demonstrate that the HIF-1 nuclear complex, formed on S1P stimulation, is transcriptionally active and specifically binds to a hypoxia-responsive elements. Moreover, S1P activates the expression of genes known to be closely regulated by HIF-1.

Conclusion— Our results identify S1P as a novel and potent nonhypoxic activator of HIF-1. We believe that understanding the role played by HIF-1 in S1P gene regulation will have a strong impact on different aspects of vascular biology.

This study demonstrates that sphingosine-1-phosphate (S1P) is a potent activator of hypoxia-inducible factor-1 (HIF-1) in vascular cells. Increases in cellular levels of HIF-1 is involved in S1P-mediated gene induction under normal oxygen conditions. We conclude that S1P is a novel nonhypoxic activator of HIF-1.

Key Words: sphingosine 1-phosphate • hypoxia-inducible factor-1 • gene expression • endothelial cells • vascular smooth muscle cells