University of California Los Angeles School of Medicine, Department of Anesthesiology, BH-160CHS, 650 Charles Young Drive, Los Angeles, CA 90095-7115, USA.
Am J Respir Crit Care Med. 2011 Sep 15;184(6):715-23. doi: 10.1164/rccm.201101-0078OC. Epub 2011 Jun 23.
Pulmonary hypertension (PH) is characterized by progressive increase in pulmonary artery pressure leading to right ventricular (RV) hypertrophy, RV failure, and death. Current treatments only temporarily reduce severity of the disease, and an ideal therapy is still lacking.
Estrogen pretreatment has been shown to attenuate development of PH. Because PH is not often diagnosed early, we examined if estrogen can rescue preexisting advanced PH.
PH was induced in male rats with monocrotaline (60 mg/kg). At Day 21, rats were either treated with 17-β estradiol or estrogen (E2, 42.5 μg/kg/d), estrogen receptor-β agonist (diarylpropionitrile, 850 μg/kg/d), or estrogen receptor α-agonist (4,4',4"-[4-Propyl-(1H)-pyrazole-1,3,5-triyl] trisphenol, 850 μg/kg/d) for 10 days or left untreated to develop RV failure. Serial echocardiography, cardiac catheterization, immunohistochemistry, Western blot, and real-time polymerase chain reaction were performed.
Estrogen therapy prevented progression of PH to RV failure and restored lung and RV structure and function. This restoration was maintained even after removal of estrogen at Day 30, resulting in 100% survival at Day 42. Estradiol treatment restored the loss of blood vessels in the lungs and RV. In the presence of angiogenesis inhibitor TNP-470 (30 mg/kg) or estrogen receptor-β antagonist (PHTPP, 850 μg/kg/d), estrogen failed to rescue PH. Estrogen receptor-β selective agonist was as effective as estrogen in rescuing PH.
Estrogen rescues preexisting severe PH in rats by restoring lung and RV structure and function that are maintained even after removal of estrogen. Estrogen-induced rescue of PH is associated with stimulation of cardiopulmonary neoangiogenesis, suppression of inflammation, fibrosis, and RV hypertrophy. Furthermore, estrogen rescue is likely mediated through estrogen receptor-β.
肺动脉高压（PH）的特征是肺动脉压逐渐升高，导致右心室（RV）肥大、RV 衰竭和死亡。目前的治疗方法只能暂时减轻疾病的严重程度，仍然缺乏理想的治疗方法。
雌激素预处理已被证明可以减轻 PH 的发展。由于 PH 通常不能早期诊断，我们研究了雌激素是否可以挽救已经存在的晚期 PH。
用单环酸（60mg/kg）诱导雄性大鼠 PH。第 21 天，大鼠分别用 17-β 雌二醇或雌激素（E2，42.5μg/kg/d）、雌激素受体-β 激动剂（二芳基丙腈，850μg/kg/d）或雌激素受体-α 激动剂（4,4',4"-[4-丙基-（1H）-吡唑-1,3,5-三基]三苯酚，850μg/kg/d）治疗 10 天，或不治疗以发展 RV 衰竭。进行连续超声心动图、心导管检查、免疫组织化学、Western blot 和实时聚合酶链反应。
雌激素治疗可防止 PH 进展为 RV 衰竭，并恢复肺和 RV 的结构和功能。即使在第 30 天去除雌激素后，这种恢复仍然持续，导致第 42 天 100%存活。雌二醇治疗恢复了肺和 RV 中血管的丧失。在血管生成抑制剂 TNP-470（30mg/kg）或雌激素受体-β拮抗剂（PHTPP，850μg/kg/d）存在的情况下，雌激素不能挽救 PH。雌激素受体-β 选择性激动剂与雌激素一样有效挽救 PH。
雌激素通过恢复肺和 RV 的结构和功能来挽救大鼠已经存在的严重 PH，即使在去除雌激素后，这种恢复仍然持续。雌激素诱导的 PH 挽救与心肺新生血管形成的刺激、炎症、纤维化和 RV 肥大的抑制有关。此外，雌激素的挽救可能是通过雌激素受体-β介导的。
