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 conditions, 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.