Int J Med Sci 2013; 10(6):771-781. doi:10.7150/ijms.5906
Endogenous Estrogen Attenuates Hypoxia-Induced Pulmonary Hypertension by Inhibiting Pulmonary Arterial Vasoconstriction and Pulmonary Arterial Smooth Muscle Cells Proliferation
Department of Pathology & Pathophysiology, Xijing Hospital, Fourth Military Medical University, NO.169 of Changle Western Street, Xi'an, 710032, China.
* These authors contributed equally to this study.
Xu D, Niu W, Luo Y, Zhang B, Liu M, Dong H, Liu Y, Li Z. Endogenous Estrogen Attenuates Hypoxia-Induced Pulmonary Hypertension by Inhibiting Pulmonary Arterial Vasoconstriction and Pulmonary Arterial Smooth Muscle Cells Proliferation. Int J Med Sci 2013; 10(6):771-781. doi:10.7150/ijms.5906. Available from http://www.medsci.org/v10p0771.htm
Exogenous estrogen was shown to exert various beneficial effects on multiple diseases including hypoxia-induced pulmonary hypertension (HPH). However, the effect of endogenous estrogen on HPH was seldom investigated. In the present study, we explored the protective effects and mechanisms of endogenous estrogen on hypoxia-induced pulmonary hypertension. Male, female, pregnant and ovariectomized rats were housed in a hypoxic condition for 21 days, and then hemodynamic together with morphologic indexes of pulmonary circulation were measured. The right ventricular systolic pressure, mean pulmonary artery pressure, right ventricular hypertrophy index, and arterial remodeling index were significantly elevated after chronic hypoxia exposure. Experimental data showed less severity in female, especially in pregnant rats. In vitro, artery rings of different sex or estrus cycle rats were obtained, and then artery rings experiments were performed to investigate pulmonary vasoconstriction by recording the maximum phase II vasoconstriction. Data showed that the vasoconstriction was milder in proestrus female than diestrus female or male groups, which could be leveled by treating U0126 (a MAPK pathway inhibitor). Pulmonary arterial smooth muscle cells isolated from different sex or estrus cycle rats were cultured in the condition of 2% oxygen for 24 hours, and cell proliferation was evaluated by the [3H]-thymidine incorporation assay. Cells from proestrus rats exhibited lower proliferation than the other groups, which could be countered by both U0126 and raloxifene (a selective estrogen receptor modulator). Serum estradiol levels were detected, and rats with higher levels showed less severity of pulmonary hypertension. Conclusively, endogenous estrogen may alleviate hypoxia-induced pulmonary hypertension by attenuating vasoconstriction through non-genomic mechanisms and inhibiting smooth muscle cells proliferation through both genomic and non-genomic mechanisms.
Keywords: Endogenous estrogen, hypoxia-induced pulmonary hypertension, pulmonary vascular remodeling, hypoxic pulmonary vasoconstriction, estrous cycle.