内皮细胞核心生物钟基因bmal1在血压稳态调控中的作用和机制研究

生物钟对维持血压的生理稳态至关重要。我们前期利用可诱导的核心生物钟基因bmal1全身敲除小鼠证实基础血压的昼夜节律主要受控于生物钟而非行为，但bmal1参与血压调控的细胞基础和分子机制，及其在高血压发生发展中的作用尚不明确。内皮细胞与血压调节密切相关，我们推测内皮细胞bmal1在维持正常血压及其昼夜节律中发挥重要作用。预实验发现敲除内皮细胞bmal1使小鼠血压下降、节律减弱，且AngII的升压效应被抑制；内皮细胞过表达bmal1可抑制血管舒张因子PGI2的分泌及其合酶PGIS的转录；提示敲除内皮细胞bmal1可减缓高血压，其机制可能与PGIS/PGI2通路的活化有关。本课题将利用内皮细胞组织特异性bmal1基因敲除或转基因小鼠，结合离体血管环和体外细胞实验，深入探讨内皮细胞bmal1在基础血压稳态维持及高血压发生发展中的作用和机制，为明晰生物钟在血压调控中的作用，及高血压的防治提供新思路。

The circadian clock is essential for the maintenance of blood pressure (BP) homeostasis. By using the inducible bmal1 global knockout mice, we recently reported that the circadian rhythm of BP is controlled by the biological clock rather than the behavior. However, the cellular and molecular mechanisms of bmal1 in BP homeostasis regulation remain unclear, and the role of bmal1 in hypertension has not been investigated yet. Vascular endothelial cells are essential for BP homeostasis. By generating a mouse line with bmal1 selectively deficient in endothelial cells (ECs) and performing preliminary experiments, we found that selective deletion of bmal1 in ECs significantly lowers basal BP and decreases its day-night variation in mice. In addition, the acute vasopressor response of AngII was also blunted when bmal1 is knockout in ECs. Therefore, we speculate that EC bmal1 is fundamental in maintaining normal BP levels and its circadian rhythm, deletion bmal1 in ECs might prevent against hypertension. Furthermore, we found that overexpression of bmal1 reduces the secretion of PGI2, an endothelium-derived vessel dilator, and inhibits the expression of PGI2 synthase (PGIS) in cultured ECs, suggesting that the BP lowering effect of EC bmal1 deletion might be attributable to the activation of endothelial PGIS/PGI2 pathway. To further verify our hypothesis, we will use two mouse lines with bmal1 either conditionally deleted or selectively overexpressed in ECs to deeply investigate the role of EC bmal1 in BP homeostasis. Mesenteric artery vascular rings and in vitro cell culture experiments will be extensively performed for exploring the underlying mechanisms. This study may provide important theoretical basis for elucidating the role of circadian clock on BP homeostasis regulation and provide new targets for the prevention and treatment of hypertension.