Progesterone inhibits vascular remodeling and attenuates monocrotaline-induced pulmonary hypertension in estrogen-deficient rats.
Progesterone inhibits vascular remodeling and attenuates monocrotaline-induced pulmonary hypertension in estrogen-deficient rats.
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发表时间：
2009-07
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通讯作者：
P. Tofovic;X. Zhang;G. Petrusevska
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作者：
P. Tofovic;X. Zhang;G. Petrusevska
(Full案文见http：//www.manu.edu.mk/prilozi）。肺动脉高压（PH）主要是年轻女性的疾病。然而，鲜为人知的是，关于女性性激素在PH的影响。雌性大鼠发展不太严重的PH相比，雄性大鼠，卵巢切除术（OVX）加剧PH。虽然OVX大鼠雌二醇治疗发展不太严重的疾病，孕酮在OVX引起的疾病恶化的作用还没有被检查。Progestrin显示扩张肺血管并抑制内皮细胞和血管平滑肌细胞的增殖。将30只雌性大鼠切除卵巢，随机给予生理盐水（OVX对照组，n = 7）、野百合碱（60 mg/kg，i. p.; OVX-MCT组（n = 12），或MCT+孕酮组（n = 11）。32天后，对动物进行仪器化以原位（开胸）测量右心室（RV）收缩期峰值（RVSP）和舒张末期（RVEDP）压力，并获得组织样品用于形态测定和组织学分析。MCT给药导致RVSP升高（22.2 +/- 1.1 vs. 46.7 +/- 2.4 mmHg）和RVEDP（1.51 +/- 0.86 vs. 11.9+/-2.2 mmHg），RV/左心室+室间隔（RV/LV+S）比值增加（0.256 +/- 0.010 vs. 0.582 +/- 0.033，OVX vs. OVX-MCT），并诱导小尺寸肺动脉的中膜肥大。在卵巢切除的肺动脉高压大鼠中，孕酮治疗减轻了疾病的严重程度（OVX-MCT+P组：RVSP = 36.6 +/- 2.3 mmHg; RV/LV+S = 0.468 +/- 0.025; RVEDP = 7.5 +/-1.5 mmHg），血管重塑减弱（中位%指数：28.2 +/- 1.1对比34.2 +/- 1.3）和降低的死亡率（9%对比25%; OVX-MCT+P对比OVX-MCT）。这项研究提供了第一个证据表明，在雌激素缺乏的大鼠，孕酮在MCT诱导的PH中具有保护作用。需要进一步评估孕酮的作用及其与雌激素在肺动脉高压中的相互作用。关键词：肺动脉高压，预后，雌激素，血管重构。
(Full text is available at http://www.manu.edu.mk/prilozi). Pulmonary arterial hypertension (PH) is predominantly a disease of young females. Yet, little is known regarding the effects of female sex hormones in PH. Female rats develop less severe PH compared to male rats, and ovariectomy (OVX) exacerbates PH. Although OVX rats treated with estradiol develop less severe disease, the role of progesterone in OVX-induced exacerbation of disease has not been examined. Progesterone was shown to dilate pulmonary vessels and to inhibit proliferation of endothelial and vascular smooth muscle cells. Therefore, we hypothesized that progesterone may confer protective effects in experimental PH. A total of 30 female rats were ovariectomized and OVX rats were randomly administered either saline (OVX-Control group, n = 7), monocrotaline (60mg/kg i.p.; OVX-MCT group; n = 12), or MCT plus progesterone (30microg/kg/h via osmotic minipumps; OVX-MCT+P group; n = 11). After 32 days animals were instrumented for in situ (open chest) measurements of right ventricle (RV) peak systolic (RVSP) and end diastolic (RVEDP) pressures, and tissue samples were obtained for morphometric and histological analysis. Administration of MCT elevated RVSP (22.2 +/- 1.1 vs. 46.7 +/- 2.4 mmHg) and RVEDP (1.51 +/- 0.86 vs. 11.9+/-2.2 mmHg), increased RV/left ventricle + septum (RV/LV+S) ratio (0.256 +/- 0.010 vs. 0.582 +/- 0.033, OVX vs. OVX-MCT), and induced media hypertrophy of small size pulmonary arteries. In ovariectomized pulmonary hypertensive rats, treatment with progesterone attenuated the severity of disease (OVX-MCT+P group: RVSP = 36.6 +/- 2.3 mmHg; RV/LV+S = 0.468 +/- 0.025; RVEDP = 7.5 +/-1.5 mmHg), attenuated vascular remodeling (media % index: 28.2 +/- 1.1 vs. 34.2 +/- 1.3), and reduced mortality (9% vs. 25%; OVX-MCT+P vs. OVX-MCT). This study provides the first evidence that in estrogen-deficient rats, progesterone has protective effects in MCT-induced PH. Further evaluation of the role of progesterone and its interaction with estrogens in pulmonary hypertension is warranted. Key words: Pulmonary Hypertension, Progesterone, Estrogens, Vascular remodeling.