Abstract
Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (BMPR2; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans. In this narrative review, we explore the complex interplay between the BMP and estrogen signaling pathways, and the potentially synergistic mechanisms by which these signaling cascades increase the risk of developing PAH. A comprehensive understanding of these tangled pathways may reveal therapeutic targets to prevent or slow the progression of PAH.
Highlights
Group 1 pulmonary hypertension is a rare disease characterized by remodeling of the small pulmonary arteries which leads to the progressive elevation of pulmonary vascular resistance (PVR), and to right ventricular failure and death
Studies of pulmonary hypertension (PH) in several distinct rat models have demonstrated that at baseline female rats have better right ventricular (RV) function than males [19], ovariectomy attenuates the beneficial effect of female sex [19], and that the restoration of estrogen signaling prevents progression of and can rescue the failing RV phenotype in both male and female rats via alterations in metabolism, inflammation, collagen deposition/fibrosis, and angiogenesis [19,20,21,22,23,24]
In keeping with this finding, female hPASMCs are more proliferative in response to mitogens compared to male cells and have reduced induction of phosphorylated-Smads when exposed to BMP4, an agonist of
Summary
Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries which leads to the progressive elevation of pulmonary vascular resistance (PVR), and to right ventricular failure and death. Heterozygous germline mutations in BMPR2 were first associated with PAH via genetic linkage analysis of families with the disease [3,4]. Since this discovery in 2000, further analysis of up- and down-stream signaling through the receptor, including both canonical and non-canonical pathways, has illuminated several mechanisms by which deficiency in BMPR2 signaling leads to PAH [5]. Despite the strong association between BMPR2 mutations and the development of PAH, and despite the high frequency of BMPR2 mutations in heritable PAH, having a BMPR2 mutation alone is not sufficient; heterozygous carriers of deleterious BMPR2 mutations only have an approximately 20% lifetime risk of disease penetrance [15]. Decades of investigation have revealed that there are likely multiple genetic and environmental “second hits” that may be necessary to spur PAH development in the setting of a deleterious BMPR2 mutation [2]
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