Oestrogen receptor alpha identified as right ventricle protector in pulmonary hypertension

Researchers have identified a mechanism that may help explain why women with pulmonary hypertension can maintain better right-heart function than men, despite facing a higher risk of developing some forms of the disease.

The preclinical study led by scientists at National Jewish Health found that oestrogen receptor alpha (ERα) helps preserve the blood vessels supplying the right side of the heart during pulmonary hypertension. The findings suggest the receptor could provide a potential target for therapies designed specifically to protect the right ventricle. 

Protecting the right ventricle

Pulmonary hypertension occurs when blood pressure in the vessels of the lungs becomes abnormally high. This forces the right ventricle, which pumps blood through the lungs, to work harder.

How well the right ventricle adapts to this increased workload is a major factor in determining outcomes for people with pulmonary hypertension. Although women are more likely to develop certain forms of the condition, their right ventricles can often function better than those of men.

Researchers have been investigating the biological mechanisms that could explain this apparent sex difference.

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. 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.”

Dr Tim Lahm, MD, Researcher, National Jewish Health

Maintaining the heart’s blood vessels

The research team used preclinical models of pulmonary hypertension and right ventricular pressure overload to examine the role of ERα in endothelial cells. These cells line blood vessels and are essential for maintaining the vascular network that supplies tissues with oxygen and nutrients.

When normal ERα activity was disrupted, endothelial cells became less capable of migrating and forming vessel-like networks. They also struggled to maintain the small blood vessels needed to support the right ventricle under pressure.

The effects were particularly pronounced in female models. Impaired ERα function was associated with increased endothelial cell death, reduced capillary density and greater enlargement of the right ventricle.

The findings suggest that maintaining a healthy network of small blood vessels could be an important part of how the right heart adapts to pulmonary hypertension. 

Evidence of a sex-specific mechanism

The researchers used single-nucleus RNA sequencing to examine changes in gene activity within individual cell populations.

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. The same changes were not seen to the same extent in males.

This provides further evidence that ERα may have a sex-specific role in protecting the right ventricle during pulmonary hypertension.

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

Dr Tim Lahm, MD, Researcher, National Jewish Health

Potential route to new treatments

The findings could help researchers develop treatments aimed specifically at protecting the right ventricle rather than focusing solely on reducing pressure in the pulmonary arteries.

However, the research does not establish that oestrogen or treatments targeting ERα would be safe or effective for people with pulmonary hypertension, as these findings are still preclinical.

Further studies will be needed to confirm whether the mechanism operates in patients and determine whether it can be targeted without producing unwanted effects elsewhere in the body.

The researchers say the work nevertheless provides a potential new biological target for developing therapies designed to preserve the right ventricle and its blood supply as pulmonary hypertension progresses.