Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: A humoral mechanism to reset a peripheral clock

Circadian clock genes are expressed in the suprachiasmatic nucleus and in p eripheral tissues to regulate cyclically physiological processes. Synchroni zation of peripheral oscillators is thought to involve humoral signals, but the mechanisms by which these are mediated and integrated are poorly under stood. We report a hormone-dependent interaction of the nuclear receptors, RAR alpha and RXR alpha, with CLOCK and MOP4. These interactions negatively regulate CLOCK/MOP4: BMAL1-mediated transcriptional activation of clock ge ne expression in vascular cells. MOP4 exhibits a robust rhythm in the vascu lature, and retinoic acid can phase shift Per2 mRNA rhythmicity in vivo and in serum-induced smooth muscle cells in vitro, providing a molecular mecha nism for hormonal central of clock gene expression. We propose that circadi an or periodic availability of nuclear hormones may play a critical role in resetting a peripheral vascular clock.