Study Identifies Estrogen Receptor as Key Protector of the Right Heart in Pulmonary Hypertension


DENVER - Researchers at National Jewish Health have identified a key way estrogen receptor alpha (ERα) helps protect the right side of the heart in pulmonary hypertension. The preclinical findings reveal that ERα preserves the survival and movement of endothelial cells, which line blood vessels, allowing the stressed heart to maintain the small vessels it needs to function.

The study, published online Sept. 10 in Arteriosclerosis, Thrombosis, and Vascular Biology, may help explain an important difference between women and men with pulmonary hypertension and points to a potential path for developing therapies tailored to the right ventricle, the chamber that pumps blood through the lungs.

Pulmonary hypertension causes abnormally high pressure in the blood vessels of the lungs. That pressure forces the right ventricle to work harder, and a patient's outlook depends heavily on how well the chamber adapts. Although women are more likely to develop certain forms of pulmonary hypertension, their right ventricles often function better than those of men. Researchers have been working to understand the biology behind that apparent paradox.

"We know that the right ventricle is a major driver of survival in pulmonary hypertension, but we still have very few treatments designed specifically to protect it," said pulmonologist Tim Lahm, MD, senior author of the study and a researcher at National Jewish Health. "These findings show that estrogen receptor alpha is doing important work inside the blood vessels of the right heart, particularly in females, by helping endothelial cells survive, move and build the vascular network the heart needs under stress."

Using preclinical models of pulmonary hypertension and right ventricular pressure overload, researchers examined how ERα affects the endothelial cells that line blood vessels in the right side of the heart. When normal ERα function was disrupted, these cells were less able to migrate, form vessel-like networks and maintain the capillaries needed to support the heart under increased pressure. The effects were more pronounced in females and included increased endothelial cell death, greater enlargement of the right ventricle and reduced capillary density.

Single-nucleus RNA sequencing provided additional insight into the underlying mechanisms. In females with impaired ERα function, endothelial cells showed reduced activity in pathways involved in cell movement and increased activity in pathways associated with cell death. These changes were not observed to the same degree in males, further supporting a sex-specific role for the receptor.

“A healthy network of capillaries is essential when the right ventricle is working against increased pressure,” Dr. Lahm said. “By showing how ERα supports that network, this work gives us a more precise biological target to investigate.”

The findings do not establish estrogen or ERα-targeted therapy as a treatment for patients yet, but are an important first step. Additional research is needed to confirm the mechanism in people and determine whether it can be translated into a safe and effective therapy.
 

National Jewish Health is the leading respiratory hospital in the nation delivering excellence in multispecialty care and world class research. Founded in 1899 as a nonprofit hospital, National Jewish Health today is the only facility in the world dedicated exclusively to groundbreaking medical research and treatment of children and adults with respiratory, cardiac, immune and related disorders. Patients and families come to National Jewish Health from around the world to receive cutting-edge, comprehensive, coordinated care. To learn more, visit njhealth.org or the media resources page.


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