2-Methoxyestradiol Attenuates the Development and Retards the Progression of Hypoxia-And Alpha-Naphthylthiourea-Induced Pulmonary Hypertension

Abstract Pulmonary arterial hypertension (PH), a progressive, incurable, and deadly disease, predominantly develops in women. Growing body of evidence suggest that dysregulated estradiol (E2) metabolism influences the development PH some biological effects E2 are mediated by its major non-estrogenic metabolite, 2-metyhoxyestradiol (2ME). The objective this study was to examine 2ME chronic hypoxia (CH)-induced alpha-naphthylthiourea (ANTU)-induced acute lung injury PH. In addition, we investigated exposure different levels CH on Chronic 15% or 10% oxygen produced similar increases right ventricle peak systolic pressure (RVPSP) pulmonary vascular remodeling, but concentration-dependent increase hematocrit. Notably, (RV) hypertrophy correlated with level hematocrit, rather than magnitude RVPSP. latter suggests that, addition increased afterload, (via hematocrit) significantly contributes RV model CH-PH rats, preventive curative treatments reduced both elevated RVPSP remodeling. Curative treatment more effective reducing hematocrit ventricular hypertrophy, as compared treatment. Single ANTU injection injury, i.e., lungs weight induced pleural effusion. Treatment effusion and, importantly, eliminated mortality (33% vs 0%, vs. ANTU+2ME group). weight. 2-ME attenuated severity disease (i.e., RVPSP, injury). This demonstrates has beneficial hypoxia- injury-induced provides preclinical justification for clinical evaluation hypertension.