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

Pulmonary arterial hypertension: Sex matters

“…There is also anecdotal evidence of progesterone receptor expression in the plexiform lesions of a PAH patient, localised to myofibroblasts and modified ECs (Barberis et al, 1995). Furthermore, progesterone offsets the development of PH in ovariectomised female monocrotaline rats, by inhibiting vascular and cardiac remodelling and improving survival (Tofovic, Zhang, & Petrusevska, 2009). Further studies of role of progesterone in PAH pathobiology are clearly warranted.…”

Sex Differences in Pulmonary Hypertension

“…Similarly, female adult rats present better adaptation with lower PAP than males ( Rabinovitch et al, 1981 ), that worsens after ovariectomy which may be attenuated through estrogens administration ( Earley and Resta, 2002 ). In addition, very recently it has been shown that 2 ME abolishes hypoxia-induced PH in rats associated with a reduced protein expression of hypoxia-inducible factor 1α protein expression, a pro-proliferative mediator ( Docherty et al, 2019 ), reversion of the downregulation of miR-223 ( Hao et al, 2019 ), inhibition of endothelin gene expression ( Earley and Resta, 2002 ) and reducing hematocrit ( Tofovic et al, 2021 ), all suggesting that in female rodents female sex hormones are protective against PH. However, this model translates poorly to human PAH as it lacks some of the main human characteristics of PAH as plexiform lesions and severe RV failure, and PH is almost reversible if the animal is re-exposed to normal room air ( Stenmark et al, 2006 ).…”

Heterozygous Tropomodulin 3 mice have improved lung vascularization after chronic hypoxia

“…In order to rule out any hormonal-related influence on pulmonary hypertension during the estrous cycle (41), all animal experiments were conducted in male mice (8-10 weeks old, ∼25 g body weight). Animal care and handling was performed according to the NIH guidelines.…”