Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Am J Respir Crit Care Med. 2012 May 1;185(9):965-80. doi: 10.1164/rccm.201107-1293OC. Epub 2012 Mar 1.
17β-Estradiol (E2) attenuates hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension (HPH) through an unknown mechanism that may involve estrogen receptors (ER) or E2 conversion to catecholestradiols and methoxyestradiols with previously unrecognized effects on cardiopulmonary vascular remodeling.
To determine the mechanism by which E2 exerts protective effects in HPH.
Male rats were exposed to hypobaric hypoxia while treated with E2 (75 μg/kg/d) or vehicle. Subgroups were cotreated with pharmacologic ER-antagonist or with inhibitors of E2-metabolite conversion. Complementary studies were performed in rats cotreated with selective ERα- or ERβ-antagonist. Hemodynamic and pulmonary artery (PA) and right ventricular (RV) remodeling parameters, including cell proliferation, cell cycle, and autophagy, were measured in vivo and in cultured primary rat PA endothelial cells.
E2 significantly attenuated HPH endpoints. Hypoxia increased ERβ but not ERα lung vascular expression. Co-treatment with nonselective ER inhibitor or ERα-specific antagonist rendered hypoxic animals resistant to the beneficial effects of E2 on cardiopulmonary hemodynamics, whereas ERα- and ERβ-specific antagonists opposed the remodeling effects of E2. In contrast, inhibition of E2-metabolite conversion did not abolish E2 protection. E2-treated hypoxic animals exhibited reduced ERK1/2 activation and increased expression of cell-cycle inhibitor p27(Kip1) in lungs and RV, with up-regulation of lung autophagy. E2-induced signaling was recapitulated in hypoxic but not normoxic endothelial cells, and was associated with decreased vascular endothelial growth factor secretion and cell proliferation.
E2 attenuates hemodynamic and remodeling parameters in HPH in an ER-dependent manner, through direct antiproliferative mechanisms on vascular cells, which may provide novel nonhormonal therapeutic targets for HPH.
17β-雌二醇（E2）通过一种未知的机制减轻低氧性肺血管收缩和低氧性肺动脉高压（HPH），该机制可能涉及雌激素受体（ER）或 E2 转化为儿茶酚雌二醇和甲氧基雌二醇，对心肺血管重塑具有先前未被认识的作用。
确定 E2 在 HPH 中发挥保护作用的机制。
雄性大鼠在低气压缺氧环境下暴露，同时接受 E2（75μg/kg/d）或载体处理。亚组接受药理学 ER 拮抗剂或 E2 代谢物转化抑制剂的联合治疗。在同时接受选择性 ERα或 ERβ拮抗剂治疗的大鼠中进行补充研究。在体内和培养的原代大鼠肺动脉内皮细胞中测量血流动力学和肺动脉（PA）和右心室（RV）重塑参数，包括细胞增殖、细胞周期和自噬。
E2 显著减轻 HPH 终点。低氧增加了肺血管 ERβ但不增加 ERα的表达。非选择性 ER 抑制剂或 ERα特异性拮抗剂联合治疗使缺氧动物对 E2 对心肺血液动力学的有益作用产生抗性，而 ERα和 ERβ特异性拮抗剂则对抗 E2 的重塑作用。相比之下，抑制 E2 代谢物转化并不能消除 E2 的保护作用。E2 治疗的缺氧动物表现出 ERK1/2 激活减少和肺及 RV 中细胞周期抑制剂 p27（Kip1）表达增加，肺自噬增加。在低氧而非常氧内皮细胞中再现了 E2 诱导的信号转导，与血管内皮生长因子分泌和细胞增殖减少有关。
E2 以 ER 依赖性方式减轻 HPH 中的血流动力学和重塑参数，通过对血管细胞的直接抗增殖作用，为 HPH 提供了新的非激素治疗靶点。
