Estrogenic action on arterial smooth muscle: permissive for maintenance of CRHR2 expression.
Estrogenic action on arterial smooth muscle: permissive for maintenance of CRHR2 expression.
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DOI：
10.1210/en.2011-1939
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发表时间：
2012-02
期刊：
影响因子：
4.8
通讯作者：
Shan Wang;Xiaoyan Zhu;Binhai Cong;Xingji You;Yang-kai Wang;Wei-zhong Wang;X. Ni
中科院分区：
文献类型：
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作者：
Shan Wang;Xiaoyan Zhu;Binhai Cong;Xingji You;Yang-kai Wang;Wei-zhong Wang;X. Ni
尿皮质素 (Ucn) 是 CRH 家族的成员，被认为是心血管系统中的内源性调节剂之一，并通过自分泌/旁分泌方式在局部发挥其作用。此前的研究表明，CRH引起的人体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。本研究的目的是探讨雌激素是否调节血管平滑肌中 Ucn/CRH 受体 2 (CRHR2) 的表达，从而导致血管舒张。我们对雌性 Sprague Dawley 大鼠进行了假手术或双侧卵巢切除术 (OVX)。 OVX 大鼠皮下注射 17β-雌二醇 (E2)，剂量为 30 μg/kg·d，或与安慰剂一起注射 12 周。主动脉原代平滑肌细胞用于体外研究。结果发现，OVX 大鼠中 Ucn 诱导的血管舒张和 CRHR2 表达降低，并通过 E2 替代治疗 12 周恢复。 E2 增加培养的平滑肌细胞中 CRHR2 的表达，而雌激素受体-β 拮抗剂可阻断这种表达。 Ucn 显着抑制去氧肾上腺素诱导的磷脂酶 Cβ3 激活、肌醇 1,4,5-三磷酸 (IP₃) 产生和细胞内 Ca2+ 升高。 Ucn 刺激活性 GTP 结合 Gαs 蛋白的表达和 cAMP 的产生。 Ucn 对去氧肾上腺素诱导的 IP₃ 产生和细胞内 Ca2+ 升高的抑制作用被腺苷酸环化酶和蛋白激酶 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 信号传导发挥血管舒张作用，导致磷脂酶 Cβ-IP₃-Ca2⁺ 信号通路下调。
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.