Interaction Between Bone Morphogenetic Protein Receptor Type 2 And Estrogenic Compounds In Pulmonary Arterial Hypertension

The majority of heritable pulmonary arterial hypertension (HPAH) cases are associated with mutations in bone morphogenetic protein receptor type 2 (BMPR2). BMPR2 mutation carries about a 20% lifetime risk of PAH development, but penetrance is approximately three times higher in females. Previous studies have shown a correlation between estrogen metabolism and penetrance, with increased levels of the estrogen metabolite 16 alpha-hydroxyestrone (16 alpha OHE) and reduced levels of the metabolite 2-methoxyestrogen (2ME) associated with increased risk of disease. The goal of this study was to determine whether 16 alpha OHE increased and 2ME decreased penetrance of disease in Bmpr2 mutant mice and, if so, by what mechanism. We found that 16 alpha OHE: 2ME ratio was high in male human HPAH patients. Bmpr2 mutant male mice receiving chronic 16 alpha OHE had doubled disease penetrance, associated with reduced cardiac output. 2ME did not have a significant protective effect, either alone or in combination with 16 alpha OHE. In control mice but not in Bmpr2 mutant mice, 16 alpha OHE suppressed bone morphogenetic protein signaling, probably directly through suppression of Bmpr2 protein. Bmpr2 mutant pulmonary microvascular endothelial cells were insensitive to estrogen signaling through canonical pathways, associated with aberrant intracellular localization of estrogen receptor a. In both control and Bmpr2 mutant mice, 16 alpha OHE was associated with suppression of cytokine expression but with increased alternate markers of injury, including alterations in genes related to thrombotic function, angiogenesis, planar polarity, and metabolism. These data support a causal relationship between increased 16 alpha OHE and increased PAH penetrance, with the likely molecular mechanisms including suppression of BMPR2, alterations in estrogen receptor translocation, and induction of vascular injury and insulin resistance-related pathways.