Sex, Genetics, and the Relationship Between the Two in Pulmonary Arterial Hypertension

Although research has cemented BMPR2 mutations as having associations with the development of pulmonary arterial hypertension, the germline mutations are not the only culprit.

Pulmonary arterial hypertension (PAH) is a multifaceted condition, consisting of interactions between estrogens, estrogen metabolites, and BMPR2 signaling, according to new research.

Although research has cemented BMPR2 mutations as having associations with the development of PAH, the germline mutations are not the only culprit, say the researchers, who argue that other, additional genetic and environmental factors play a role. Mutations in several components of the BMPR2 signaling pathway have also been linked to the development of PAH, including ALK1, SMAD8, BMP9, and CAV1.

“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,” explained the researchers. “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.”

The intricacies of PAH can be highlighted by the role estrogen and estrogen metabolites play in the condition. For example, some animal models have suggested that the 2 protect against PH in the presence of other provoking factors while human studies have suggested that female predominance actually heightens the risk of PAH. And while females who carry deleterious BMPR2 variants are more likely to develop PAH, they are less likely to have severe disease than men.

However, the researchers argue that the role of estrogen and estrogen metabolites does not paint a full picture of the sex differences in PAH. These differences include those in right ventricular (RV) adaption to chronic pulmonary hypertension, with some research suggests that females might have better RV function than males. According to the researchers, other sex-driven differences, like testosterone and progesterone and nonhormonal sex effects, may contribute to the impact of sex.

“Similar to the BMPR2 signaling cascade, essential components of estrogen signaling pathways are expressed in the [endothelial cells], vascular [smooth muscle cells], and fibroblasts responsible for vascular remodeling and the development of PAH,” wrote the researchers, noting that estrone, estradiol, and estriol, along with their metabolites signal through estrogen receptors ERα and ERβ and the newly discovered G-protein-coupled receptor.

In their paper, the researchers look at the relationship between estrogen and BMPR2, writing that there have been inclinations that baseline BMPR2 expression and signaling may be reduced in females. They suggest that this deficiency in BMPR2 expression may be that “second hit” to spur the development of PAH. However, they caveat that the relationship between estrogen and BMPR2 is complex and may be dependent on several factors, such as age, menopausal status, cell type studied, and dose responses and time courses.


Cirulis MM, Dodson MW, Brown LM, Brown SM, Lahm T, Elliot G. At the X-roads of sex and genetics in pulmonary arterial hypertension. Genes (Basel). Published online November 20, 2020. doi:10.3390/genes11111371