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 a better 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 you can use medication to treat PAH symptoms and the condition itself.

The 4 Key Pathways in People With Pulmonary Arterial Hypertension

There are four pathways known to be involved in PAH. In people with PAH, one of four key natural chemicals may be out of balance in the body: activin, endothelin, nitric oxide, or prostacyclin. People with PAH usually have either too much activin or endothelin or not enough nitric oxide or prostacyclin.

In people with PAH, one of four key natural chemicals may be out of balance in the body: activin, endothelin, nitric oxide, or prostacyclin.

These chemical imbalances cause changes in the arteries of the lungs. These changes include:

• Narrowing of the vessels
• Stiffening of the vessel walls
• Scarring that can block the vessels
• Inflammation

How PAH Medications Target These Pathways

Each PAH medicine is tailored to target one of these chemical imbalances. Treating the imbalance can help reduce symptoms and slow disease progression.

Sometimes, a healthcare provider will use two or more medications to help manage PAH. This is known as combination therapy.

Activin Pathway

For years, PAH was associated with three main pathways: endothelin, nitric oxide, and prostacyclin. In 2024, a fourth pathway called activin was recognized.

Activin is a protein that belongs to the transforming growth factor-beta superfamily. Excess activin can result in worsening PAH. This is because it can cause cells in the blood vessels of the lungs to multiply and become inflamed. This activity in the blood vessel walls leads to additional strain on the heart muscle. A drug called sotatercept (Winrevair), which was approved by the U.S. Food and Drug Administration (FDA) in March 2024, works on this pathway.

Sotatercept works by trapping and neutralizing activin. Clinical trials have found that sotatercept can help with PAH in two ways — it can help improve PAH symptoms, and it can slow disease progression. It does this by stopping the chain of events that leads to increased pressure on the heart.

Healthcare providers may use the medication alone (monotherapy), or they may use it in a new combination therapy to treat multiple PAH pathways at once. If your doctor recommends sotatercept or any new PAH therapy, make sure to ask about potential side effects as well as how you’ll be monitored during follow-up to see if the medication is working.

Healthcare providers may use one medication alone (monotherapy) or more than one drug (combination therapy) to treat multiple PAH pathways at once.

Endothelin Pathway

Endothelin is a protein in the blood that helps regulate blood pressure. When endothelin levels are too high, it 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. Combined with lower-than-normal levels of prostacyclin and nitric oxide, high endothelin can cause an overall imbalance in the blood vessels of the lungs. This imbalance can lead to the narrowing of arteries and put pressure on the heart’s structures. If left untreated, this may eventually result in heart failure, with shortness of breath and leg swelling.

High endothelin-1 levels can be detected through blood testing and treated with medication to help lower endothelin-1 levels. Endothelin receptor antagonists (ERAs) have been shown to reduce blood pressure in the lungs by blocking endothelin-1 from binding 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, a combination of macitentan and tadalafil — a phosphodiesterase 5 (PDE5) inhibitor — with the brand name Opsynvi was approved 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 your blood flowing by ensuring vasodilation (widening of blood vessels) so your blood pressure levels remain stable. When nitric oxide levels are too low, the heart has to work harder to pump blood, which can contribute to PAH.

Inhaled nitric oxide isn’t routinely used in the treatment of PAH because there’s a lack of high-quality evidence to support its use, though PAH specialists may still prescribe it if your nitric oxide levels are abnormal. 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.

Inhaled nitric oxide is a targeted medication, which means it doesn’t treat your entire body. Instead, it targets your level of nitric oxide to reduce PAH symptoms. “Nitric oxide has helped improve my breathing and strength,” wrote a myPHteam member.

To use this medication, you breathe the gas in through your mouth or nose. The nitric oxide then makes its way to the area that needs it. During therapy, your doctor will monitor the oxygen levels in your blood, your pulmonary arterial pressure, and your overall blood pressure to ensure the medication is working properly.

Some oral medications also help enhance the activity of natural nitric oxide. These include 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.

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). These medications work by replacing natural prostacyclin. Options include:

• Epoprostenol (Flolan, Veletri) — Administered intravenously (into a vein)
• Iloprost (Ventavis) — Inhaled through the nose or mouth
• Selexipag (Uptravi) — Taken orally (by mouth) as a tablet
• Treprostinil (Tyvaso) — Can be taken orally, inhaled, or received intravenously

Your healthcare team can determine which of these medications might be the most effective for you. Because activin is a new pathway and sotatercept is a novel drug, your doctor might be less familiar with this PAH treatment option. If they don’t mention it, be sure to ask. If sotatercept isn’t right for you, more PAH treatments may be on the horizon.

“In addition to sotatercept (Winrevair), there are several other medications in various stages of clinical trials,” one myPHteam member 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.”

Talk With Others Who Understand

On myPHteam, the social network for people with pulmonary hypertension and their loved ones, members come together to ask questions, give advice, and share their stories.

Has your doctor mentioned that your activin, endothelin, nitric oxide, or prostacyclin levels are off? What helped manage the balance? Share your experience in the comments below, or start a conversation by posting on your Activities page.