Objective-Hypoxia-inducible factor 1␣ (HIF-1␣) is primarily involved in the adapting of cells to changes in oxygen levels, which is essential for normal vascular function. Recently, physiological roles for retinoic acid-related orphan receptor ␣ (ROR␣) have been implicated in cardiovascular diseases such as atherosclerosis. In this study, we have investigated the potential roles of ROR␣ in the hypoxia signaling pathway in connection with activation of HIF-1␣. Methods and Results -Under hypoxic

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... onditions, expression of ROR␣ was induced. When ROR␣ was introduced exogenously, protein level as well as transcriptional activity of HIF-1␣ was enhanced. Putative ligands of ROR␣, such as melatonin and cholesterol sulfate, induced transcriptional activity for HIF-1␣, which was abolished by RNA interference against ROR␣. ROR␣ was physically associated with HIF-1␣ through DNA binding domain, which was required to the ROR␣-induced stabilization and transcriptional activation of HIF-1␣. Finally, either infection with adenovirus encoding ROR␣ or treatment with ROR ligands enhanced the formation of capillary tubes by human umbilical vascular endothelial cells. Conclusions-Our results provide a new insight for the function of ROR␣ in amplification of hypoxia signaling and suggest a potential application of ROR␣ ligands for the therapy of hypoxia-associated vascular diseases. (Arterioscler Thromb Vasc Biol. 2008;28:1796-1802)