Pulmonary arterial hypertension (PAH) is a serious condition that causes high blood pressure in the arteries of the lungs. A range of therapies and medications can help people with PAH experience fewer symptoms and improve their quality of life. Some of these treatments target the molecular pathways involved in PAH.

In this article, we explore the main PAH pathways and how medication is used to treat PAH symptoms and slow the progression of the condition.

The 4 Key Pathways in People With Pulmonary Arterial Hypertension

Researchers have identified four major pathways that play a role in PAH. In people living with PAH, one or more of four key natural chemicals in the body may be out of balance:

• Activin
• Endothelin
• Nitric oxide
• Prostacyclin

People with PAH usually have either too much activin or endothelin or too little nitric oxide or prostacyclin.

People with PAH usually have either too much activin or endothelin or not enough nitric oxide or prostacyclin.

These imbalances affect how the arteries in the lungs function, leading to:

• Narrowing of the blood vessels
• Stiffening of the vessel walls
• Scarring that blocks normal blood flow
• Inflammation in the blood vessels

How PAH Medications Target These Pathways

Each PAH medication is designed to target specific chemical imbalances. By restoring balance to one or more of these pathways, treatment can help ease symptoms and slow the progression of the disease.

Oftentimes, a healthcare provider will use two or more medications to help manage a person’s PAH. This is known as combination therapy. Using multiple medications helps target more than one PAH pathway at the same time.

Activin Pathway

For years, PAH was associated with three main pathways: endothelin, nitric oxide, and prostacyclin. In 2024, a fourth pathway called activin — a protein that helps regulate cell growth and inflammation — was recognized.

In people living with PAH, high levels of activin can make the condition worse. Excess activin causes cells in the lungs’ blood vessels to multiply and become inflamed, making the vessels more stiff and narrow. This puts added strain on the right side of the heart, which has to work harder to pump blood through the lungs.

A drug called sotatercept (Winrevair), approved by the U.S. Food and Drug Administration (FDA) in March 2024, works on this pathway. It works by trapping and neutralizing activin to help restore balance.

Clinical trials have found that sotatercept can help with PAH in two ways:

• It may help improve PAH symptoms.
• It may slow the disease’s progression.

It does this by stopping the chain of events that leads to increased pressure on the right side of the heart.

Endothelin Pathway

Endothelin is a protein in the blood that helps regulate blood pressure. High endothelin levels can cause PAH. Three different types of endothelin are present in the body, but endothelin-1 has been studied the most.

Endothelin levels that are too high can cause problems when other pathways are also imbalanced. High endothelin, along with low prostacyclin and nitric oxide, can make the blood vessels in the lungs unbalanced. This can cause the arteries to narrow and increase pressure on the heart. If it is not treated, it might lead to right-sided heart failure, making it hard to breathe and causing swelling in the legs.

High endothelin-1 levels can be detected through blood testing and treated with medication to help block and lower endothelin-1 levels. Endothelin receptor antagonists (ERAs) can help lower blood pressure in the lungs by stopping endothelin-1 from attaching to cells in the body.

The FDA has approved three ERAs for the treatment of pulmonary arterial hypertension:

• Ambrisentan (sold as Letairis) — Blocks endothelin A receptors
• Macitentan (Opsumit) — Blocks both endothelin A and endothelin B receptors
• Bosentan (Tracleer) — Blocks both endothelin A and endothelin B receptors

Additionally, the FDA approved a combination of macitentan and tadalafil — a phosphodiesterase 5 (PDE5) inhibitor — with the brand name Opsynvi in March 2024.

Members of myPHteam often discuss how endothelin receptor antagonists affect their symptoms. “I was diagnosed in 2009, and the first medication I was put on treated the endothelin pathway, which was the only medication I was on till 2019,” one member wrote.

Nitric Oxide Pathway

Nitric oxide is found naturally in the human body. It is a gas that helps keep blood flowing by promoting vasodilation (widening of blood vessels), which helps maintain stable blood pressure. When nitric oxide levels are too low, the right side of the heart has to work harder to pump blood, which can cause right-sided heart failure.

Some oral (taken by mouth) medications help enhance the activity of natural nitric oxide. These include phosphodiesterase type 5 inhibitors (PDE5 inhibitors) such as sildenafil (Revatio) and tadalafil (Adcirca, Alyq).

Other medications called soluble guanylate cyclase stimulators, such as riociguat (Adempas), work slightly differently, though they also aim to increase nitric oxide levels and widen pulmonary blood vessels.

Doctors do not usually use inhaled nitric oxide to treat PAH because there’s not enough strong evidence to show it works, but some PAH specialists may still give it if your nitric oxide levels are not normal. This approach can target the blood vessels in your lungs, opening them and improving blood flow. This reverses the stress on your heart, lowering blood pressure.

“Nitric oxide has helped improve my breathing and strength,” wrote a myPHteam member.

Prostacyclin Pathway

Prostacyclin is another chemical that’s naturally present in the body. It has many roles, including:

• Reducing blood clotting and inflammation
• Relaxing pulmonary artery smooth muscle cells
• Keeping blood pressure in check

When prostacyclin levels are too low, vasoconstriction (narrowing of the lungs’ blood vessels) may occur. This can potentially lead to PAH symptoms.

To help raise prostacyclin levels, your doctor may prescribe prostacyclin analogs (prostanoids) or selective prostacyclin receptor agonists. These medications work by replacing natural prostacyclin. Options include:

• Epoprostenol (Flolan, Veletri) — Administered intravenously (into a vein)
• Iloprost (Ventavis) — Inhaled through a nebulizer
• Selexipag (Uptravi) — Taken orally as a tablet
• Treprostinil (Remodulin, Tyvaso, and Orenitram) — Can be taken orally, inhaled, injected under the skin, or received intravenously

Your healthcare team can help choose which of these medicines may work best for you. Talking openly with your healthcare team about your symptoms, concerns, and how PAH affects your daily life will help make sure you get the care you need.

“There are several other medications in various stages of clinical trials,” a member of myPHteam said. “While a PAH diagnosis is never a great thing, there is so much more information available now than ever before. We are truly pioneers changing the long-term survival rate statistics.”

“While a PAH diagnosis is never a great thing, there is so much more information available now than ever before. We are truly pioneers changing the long-term survival rate statistics.”

— A myPHteam member

Join the Conversation

On myPHteam, people share their experiences with pulmonary hypertension and pulmonary arterial hypertension, get advice, and find support from others who understand.

Has your doctor mentioned that your activin, endothelin, nitric oxide, or prostacyclin levels are off? What helped manage the balance? Let others know in the comments below.