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.

Read on to discover more about the main molecular pathways involved in PAH and how medications work to address imbalances in these pathways.

The 4 Key Pathways in People With Pulmonary Arterial Hypertension

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

Since people with PAH may have either too much or too little of one of the four signaling pathways, some PAH medicines are tailored to target one of these chemical imbalances. Treating the imbalance can help reduce symptoms and slow disease progression.

Sometimes, a health care provider will treat PAH with two or more medications — a practice known as combination therapy — to help manage the condition.

Activin

For years, PAH was associated with three main pathways: endothelin, nitric oxide, and prostacyclin. Researchers recently discovered a fourth — activin.

Activin is a protein that belongs to the transforming growth factor-beta superfamily. Excess activin can worsen PAH by causing inflammation and cell overgrowth in the blood vessel walls of the lungs, leading to additional strain on the heart muscle. A drug called sotatercept (Winrevair), approved by the U.S. Food and Drug Administration (FDA) in March 2024, may be able to help.

For years, there were three main pathways associated with PAH: endothelin, nitric oxide, and prostacyclin. Researchers recently discovered a fourth — activin.

Sotatercept works by trapping and neutralizing activin. Although clinical trials have shown that sotatercept can improve PAH symptoms, researchers noted that the drug appears to also slow disease progression by stopping the chain of events that leads to increased pressure on the heart.

More research is needed to fine-tune the use of sotatercept and ensure people with PAH get maximum benefits with minimum side effects. In the meantime, health care providers may use the medication alone or in a new combination therapy to treat multiple PAH pathways at once.

Members of myPHteam have expressed interest in having a new PAH treatment option. “Sotatercept is the latest,” one myPHteam member said. “My daughter just started it last week. It’s an injection every three weeks.”

If your doctor recommends sotatercept or any new PAH treatment, ask about potential side effects and how you’ll be monitored to see if the medication is working.

Endothelin

Endothelin is a protein in the blood that helps regulate blood pressure. When endothelin levels are too high, PAH may result. Three endothelin types are present in the body, but the one that’s been researched the most is endothelin-1.

When endothelin levels are too high and levels of prostacyclin and nitric oxide are too low, the overall imbalance causes blood vessels in the lungs’ arteries to narrow. This puts pressure on the heart’s structures and, if left untreated, 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 the volume of endothelin-1. Endothelin receptor antagonists have been shown to reduce blood pressure in the lungs by blocking endothelin-1 from binding to cells in the body.

“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.”

— A myPHteam member

The FDA has approved three endothelin receptor antagonists 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

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

Nitric oxide is found naturally in the human body. This gas helps keep blood flowing by ensuring vasodilation (that blood vessels stay open), which keeps blood pressure levels stable. When nitric oxide levels are too low, the heart has to work harder to pump blood, which can lead to PAH.

Inhaled nitric oxide isn’t routinely used in treating PAH because no high-quality studies support its effectiveness. However, PAH specialists may prescribe inhaled nitric oxide to help stabilize abnormal levels. This approach can target your lungs’ blood vessels, opening them and improving blood flow. This reverses the stress on your heart, lowering blood pressure.

Inhaled nitric oxide is considered a targeted medication rather than a systemic one — it targets your level of nitric oxide rather than treating your entire body to reduce PAH symptoms. “Nitric oxide has helped improve my breathing and strength,” one myPHteam member wrote.

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

Some oral medications also help enhance the activity of natural nitric oxide, including phosphodiesterase type 5 inhibitors such as sildenafil (Revatio) and tadalafil (Adcirca, Alyq). Another group, soluble guanylate cyclase stimulators such as riociguat (Adempas), work slightly differently but also aim to increase nitric oxide activity and widen pulmonary blood vessels.

Prostacyclin

Prostacyclin, a chemical that’s naturally present in the body, is important for reducing blood clotting and inflammation, relaxing pulmonary artery smooth muscle cells, and keeping blood pressure in check. When prostacyclin levels are too low, vasoconstriction (narrowing of the lungs’ blood vessels) may occur, potentially leading to PAH symptoms.

“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

To help raise prostacyclin levels and improve the movement of vascular smooth muscle cells, your doctor may prescribe prostacyclin analogs (prostanoids). These medications essentially take the place of natural prostacyclin. Options include:

• Epoprostenol (Flolan, Veletri) — Administered through an IV
• 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 given through an IV

Your pulmonology and cardiology care teams will work together to determine which of these medications might be the most effective for your specific situation. Because activin is a new pathway and sotatercept is a novel drug, your health care provider 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, more than 55,000 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.