The Imitation Game in Pulmonary Arterial Hypertension. Sex, Bone Morphogenetic Protein Receptor, and the Estrogen Paradox

Abstract

Estimating ground-level PM2.5 in China using satellite remote sensing. Environ Sci Technol 2014;48: 7436-7444. 16. Brunekreef B, Janssen NA, de Hartog J, Harssema H, Knape M, van Vliet P. Air pollution from truck traffic and lung function in children living near motorways. Epidemiology 1997;8:298-303. 17. Morales E, Garcia-Esteban R, de la Cruz OA, Basterrechea M, Lertxundi A, de Dicastillo MD, Zabaleta C, Sunyer J. Intrauterine and early postnatal exposure to outdoor air pollution and lung function at preschool age. Thorax 2015;70:64-73. 18. Lepeule J, Litonjua AA, Coull B, Koutrakis P, Sparrow D, Vokonas PS, Schwartz J. Long-term effects of traffic particles on lung function decline in the elderly. Am J Respir Crit Care Med 2014;190: 542-548. Bone morphogenetic protein receptor type 2 (BMPR2) mutations account for approximately 75% of hereditary pulmonary arterial hypertension (HPAH) cases and 25% of sporadic idiopathic PAH cases (1). Although BMPR2 mutations are inherited in an autosomal-dominant fashion, the penetrance of these mutations in HPAH is only approximately 30% (1). This incomplete penetrance strongly suggests the presence of additional genetic and/or environmental disease-modifying factors. Interestingly, in BMPR2 mutation carriers, the female penetrance is around 40%, whereas male penetrance is around 14% (2). Multiple studies have demonstrated that the prevalence of idiopathic PAH and HPAH is significantly higher in females (reviewed by Umar and colleagues [3] and Austin and colleagues [4]). In contrast, when compared with women, men with PAH have worse right ventricular function and survival, and in the monocrotaline and hypoxia (but not in the SU5416/hypoxia) rodent models of PH, female sex has a protective effect (reviewed by Umar and colleagues [3] and Austin and colleagues [4]).Efforts to reconcile this "estrogen paradox" (3, 4) have revealed a complex interplay between multiple facets of estrogen metabolism and BMP signaling, as well as limitations of rodent models of PH. The vascular protective effects of estradiol in experimental PH appear to be largely regulated by its nonestrogenic metabolites, 2-hydroxyestriadiol (2-OHE) and 2-methoxyestrone (2-ME). Both of these metabolites have been shown to attenuate monocrotaline-induced PH as well as hypoxiainduced PH in male rats (5, 6). 2-ME also abolishes the mortality induced by ovariectomy in monocrotaline PH (6). The effects of estrogen (and other sex hormones) are also likely to be cell/ tissue-specific and context-specific. For example, the effects of estradiol on BMP signaling in endothelial cells have been shown to shift from augmentation to inhibition when studied under normoxic versus hypoxic conditions, respectively (7). In addition, studies in BMPR2 mutation carriers have highlighted the importance of active estrogen metabolites other than 2-OHE and 2-ME in mediating increased PAH penetrance. West et al first demonstrated significantly decreased transcript levels of CYPB1, a cytochrome p450 family enzyme critical to estrogen metaboli...

Methamphetamine-associated pulmonary arterial hypertension: data from the national biological sample and data repository for pulmonary arterial hypertension (PAH Biobank)

“…However, the exact mechanisms behind this phenomenon are still not fully understood. This phenomenon was previously reported in IPAH 20 and other PAH subgroups such as connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and portopulmonary hypertension-associated PAH. 21 22 Our understanding of sex differences in MA-PAH remains limited.…”

Human iPSCs as Model Systems for BMP-Related Rare Diseases

“…In a recent study released as preprint, HPAH patient derived iPSCs were also differentiated into vascular SMCs [193]. The study suggests that progesterone promotes the proliferation and migration of HPAH iPSCs-derived VSMCs, supporting a model that describes why penetrance for BMPR2 mutation carriers is observed with a female-sex bias [194][195][196].…”

Update in Pulmonary Vascular Disease 2015

“…The importance of male or female sex as a factor in PAH prevalence, clinical outcome, and treatment response has been investigated previously (21). This year, fresh data shed novel light on the potential biomarker role of sex hormone levels in PAH.…”