Researchers Find That Estrogen Receptor Alpha is Linked to Pulmonary Hypertension Development

Researchers at the University of Glasgow and Glasgow Caledonian University in the United Kingdom published in the journal Cardiovascular Research findings revealing that that a specific receptor of the hormone estrogen is involved in the development of pulmonary hypertension. The findings may offer new insights into why PH disproportionately affects women. The study is entitled “Oestrogen receptor alpha in pulmonary hypertension.”

Pulmonary arterial hypertension is a life-threatening condition characterized by an increase of blood pressure in the pulmonary arteries that supply blood to the lungs, leading to vascular remodeling, increased pulmonary vascular resistance, difficulties in breathing, right-sided heart failure and eventually death. Overall, patients with this disorder have a poor prognosis.

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Pulmonary arterial hypertension has been reported to frequently occur in women with mutations in a specific gene, bone morphogenetic protein receptor type 2 (BMPR2), suggesting that dysfunctional BMPR2 signaling is linked to pulmonary arterial hypertension.

Researchers have previously reported that the chemical serotonin is linked to a pulmonary hypertensive phenotype in mice with defective BMPR2 expression. In addition, the hormone estrogen was found to be able to increase serotonin signaling in human pulmonary arterial smooth muscle cells (hPASMCs). Based on these observations, the aim of the study was to determine the expression of estrogen receptors in human pulmonary arteries from both male and female patients with pulmonary arterial hypertension, and to evaluate the possible role played by estrogen and serotonin on expression of BMPR2 and estrogen receptors.

The research team performed immunohistochemistry analysis in human pulmonary arteries and found that estrogen receptors like estrogen receptor alpha, estrogen receptor beta and G-protein-coupled receptor are all expressed in these arteries, being mainly localized to the smooth muscle layer that also expresses the serotonin transporter (SERT). Estrogen receptor alpha protein expression was found to be higher in hPASMCs from female patients with pulmonary arterial hypertension in comparison to male. Estrogen was found to induce the proliferation of hPASMCs through the specific activation of estrogen receptor alpha, which in turn resulted in the involvement of known regulators of cellular functions, the mitogen-activated protein kinase and Akt signaling. Serotonin was found to increase the expression of estrogen receptor alpha.

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Female mice models over-expressing SERT (SERT+) were found to develop pulmonary arterial hypertension, and the use of an antagonist to block the estrogen receptor alpha was found to attenuate pulmonary hypertension development in these SERT+ mice and to increase BMPR2 expression in the mouse lung.

The research team concluded that the estrogen receptor alpha is responsible for regulating the estrogen-induction of hPASMCs proliferation, being highly expressed in hPASMCs from female patients with pulmonary arterial hypertension. Serotonin was found to be involved with the increase in estrogen receptor alpha expression in hPASMCs and blockade of this receptor reverses the serotonin-dependent pulmonary arterial hypertension in mice and increases the expression of BMPR2, suggesting a potential new therapeutic strategy for pulmonary hypertension.

What These Findings Mean For PH Patients

More than simply determining that estrogen is linked to the onset of PH in women, the researchers were able to pinpoint higher levels of estrogen receptor alpha protein expression in the smooth muscle cells taken from the pulmonary artery in test subjects with PAH. This is a significant discovery because the researchers determined that new PAH therapies could be developed that treat the disease by blocking the receptor, as was performed on mice in the study. When estrogen receptor alpha was blocked in mice that were predisposed to develop PAH, it led to a reduction in the development of the disease. Researchers believe that the same can possibly be achieved in humans as well.