Abstract 049: Role of Smooth Muscle BMAL1 in Time-of-day Vasoconstriction Variation and Blood Pressure Circadian Rhythm

Abstract

The blood pressure circadian rhythm was believed to be primarily controlled by the central pacemaker suprachiasmatic nucleus (SCN). This dogma was challenged by the discoveries that each of the clock genes present in the SCN are also expressed and function in peripheral tissues. But whether, and if so how, the peripheral clock genes are involved remains uncertain. The current study investigates the role of Bmal1, an obligatory core clock gene, plays in smooth muscle and blood pressure regulation by using a smooth muscle specific BMAL1 knockout mouse model (SM-Bmal1-KO). The results show: 1) Smooth muscle specific deletion of BMAL1 does not affect the clock genes in SCN but drastically suppresses the amplitude and the time-of day differences in vasoconstriction in response to various agonist stimulation and to perfusion pressure increase in isolated small mesenteric arteries and pressor responses in anesthetized mice; 2) The inhibition of agonist-induced vasoconstriction is associated with suppression of MLC 20 phosphorylation, ROCK2 mRNA and activity. Moreover, BMAL1 directly binds to ROCK2 promoter in a time-of-day dependent manner in mesenteric arteries and is required for ROCK2 promoter activity in cultured vascular smooth muscle cells; 3) Mice lacking smooth muscle BMAL1, but not those lacking cardiomyocyte BMAL1, exhibits alterations in blood pressure. SM-Bmal1-KO mice have moderately but significantly decreased blood pressure under 12:12 light/dark cycle, constant dark, and constant light conditions. The blood pressure circadian rhythm in SM-Bmal1-KO mice has diminished amplitude, forward shifted acrophase, but normal period length and normal locomotor activity; 4) interestingly, pulse pressure is markedly elevated and the pulse pressure circadian rhythm is abolished in the SM-Bmal1-KO mice. These data provide novel mechanistic insights into the daily control of vasoconstriction and blood pressure, which are fundamentally significant for the elucidation of pathogenesis of diseases involving blood pressure circadian rhythm disruption.