Estradiol metabolites attenuate monocrotaline-induced pulmonary hypertension in rats

Pulmonary arterial hypertension (PH) is a deadly disease characterized by pulmonary arterial vasoconstriction and hypertension, pulmonary vasculature remodeling, and right ventricular hypertrophy. Our previous in vivo studies, performed in several models of cardiac, vascular, and/or renal injury, suggest that the metabolites of 17 beta-estradiol may inhibit vascular and cardiac remodeling. The goal of this study was to determine whether 2-methoxyestradiol (2ME), major non-estrogenic estradiol metabolite, prevents the development and/or retards the progression of monocrotaline (MCT)-induced PH. First, a total of 27 male Sprague Dawley rats were injected with distillated water (Cont, n = 6) or monocrotaline (MCT; 60 mg/kg, i.p.; n = 21). Subsets of MCT animals (n = 7 per group) received 2ME or its metabolic precursor 2-hydroxyestradiol (2HE; 10 mu g/kg/h via osmotic minipumps) for 21 days. Next, an additional set (n = 24) of control and MCT rats was monitored for 28 days, before right ventricular peak systolic pressure (RVPSP) was measured. Some pulmonary hypertensive animals (n = 8) were treated with 2ME (10 mu g/kg/h) beginning from day 14 after MCT administration. MCT caused pulmonary hypertension (ie, increased right ventricle/left ventricle + septum [RV/LV+S] ratio and wall thickness of small-sized pulmonary arteries, and elevated RVPSP) and produced high and late (days 22 to 27) mortality. Pulmonary hypertension was associated with strong proliferative response (PCNA staining) and marked inflammation (ED1 + cells) in lungs. Both metabolites significantly attenuated the RV/LV+S ratio and pulmonary arteries media hypertrophy and reduced proliferative and inflammatory responses in the lungs. Furthermore, in diseased animals, 2ME (given from day 14 to 28) significantly decreased RVPSP, RV/LV+S ratio and wall thickness, and reduced mortality by 80% (mortality rate: 62.5% vs. 12.5%, MCT vs. MCT+2ME day 14 to 28). This study provides the first evidence that 2ME, a major non-estrogenic, non-carcinogenic metabolite of estradiol, prevents the development and retards the progression of monocrotaline-induced pulmonary hypertension. Further evaluation of 2ME for management of pulmonary arterial hypertension is warranted.