Department of Physiology and The Key Laboratory of Molecular Neurobiology of Ministry of Education, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
Endocrinology. 2012 Apr;153(4):1915-24. doi: 10.1210/en.2011-1939. Epub 2012 Feb 7.
Urocortin (Ucn), a member of CRH family, has been implicated to be one of the endogenous regulators in the cardiovascular system and exerts its effects locally via an autocrine/paracrine fashion. Previous studies have shown the gender difference in CRH-induced vasodilation in human skin, which is related to the concentration of estrogens during the menstrual cycle. The aim of this study was to investigate whether estrogens modulate Ucn/CRH receptor type 2 (CRHR2) expression in vascular smooth muscle, thereby leading to vasodilation. We performed sham operation or bilateral ovariectomy (OVX) on female Sprague Dawley rats. OVX rats were sc administered 17β-estradiol (E₂) at a dose of 30 μg/kg·d or with placebo for 12 wk. Primary smooth muscle cells of aorta were used for the in vitro study. It was found that the Ucn-induced vasodilation and CRHR2 expression were decreased in OVX rats and restored by E₂ replacement treatment for 12 wk. E₂ increased the expression of CRHR2 in cultured smooth muscle cells, which was blocked by estrogen receptor-β antagonist. Ucn significantly suppressed the phenylephrine-induced phospholipase Cβ3 activation, inositol 1,4,5-trisphosphate (IP₃) production, and intracellular Ca²⁺ elevation. Ucn stimulated the expression of active GTP-bound Gαs protein and cAMP production. The suppressive effects of Ucn on phenylephrine-induced IP₃ production and intracellular Ca²⁺ elevation were blocked by the inhibitors of adenylate cyclase and protein kinase A. Our results demonstrate that estrogen maintains the expression of CRHR2 in aorta smooth muscle, thereby enhancing vasodilator actions of Ucn. Ucn exerts its vasorelaxant effects via Gαs-cAMP-protein kinase A signaling, leading to down-regulation of the phospholipase Cβ-IP₃-Ca²⁺ signaling pathway.
加压素（Ucn）是促肾上腺皮质激素释放激素（CRH）家族的一员，被认为是心血管系统的内源性调节剂之一，通过自分泌/旁分泌方式发挥作用。先前的研究表明，CRH 诱导的人皮肤血管舒张存在性别差异，这与月经周期中雌激素的浓度有关。本研究旨在探讨雌激素是否调节血管平滑肌中的 Ucn/CRH 受体 2（CRHR2）表达，从而导致血管舒张。我们对雌性 Sprague Dawley 大鼠进行假手术或双侧卵巢切除术（OVX）。OVX 大鼠每天皮下给予 17β-雌二醇（E₂）30μg/kg 或安慰剂 12 周。使用主动脉原代平滑肌细胞进行体外研究。结果发现，OVX 大鼠 Ucn 诱导的血管舒张和 CRHR2 表达减少，E₂ 替代治疗 12 周可恢复。E₂ 增加了培养的平滑肌细胞中 CRHR2 的表达，而雌激素受体-β拮抗剂可阻断这种作用。Ucn 可显著抑制去甲肾上腺素诱导的磷脂酶 Cβ3 激活、三磷酸肌醇（IP₃）生成和细胞内 Ca²⁺升高。Ucn 刺激活性 G 蛋白结合 Gαs 蛋白和 cAMP 的产生。Ucn 对去甲肾上腺素诱导的 IP₃ 生成和细胞内 Ca²⁺升高的抑制作用被环腺苷酸酶和蛋白激酶 A 抑制剂阻断。我们的结果表明，雌激素维持主动脉平滑肌中 CRHR2 的表达，从而增强 Ucn 的血管舒张作用。Ucn 通过 Gαs-cAMP-蛋白激酶 A 信号通路发挥其血管舒张作用，导致磷脂酶 Cβ-IP₃-Ca²⁺信号通路下调。
