Wanting More Wnt: New Mechanism Underlying Pulmonary Arterial Hypertension

By Adrienne Mueller, PhD
June 14, 2023

Pulmonary arterial hypertension is a chronic disease in which individuals find it harder and harder to breathe – eventually leading to right heart failure and death. Between 500 to 1000 new cases of pulmonary arterial hypertension, or PAH, are diagnosed in the US every year. PAH is characterized by the loss of small blood vessels around the lungs. Reduced blood flow from lung microvessels raises patients’ blood pressure, causing their hearts to work harder until they ultimately give out. Normally, endothelial cells in the blood vessels can help regenerate lost or damaged blood vessels, however in PAH, this process is impaired.

Previous research has shown that a cellular signaling pathway involving Wnt proteins can control the development and repair of new blood vessels around the lungs, but how the Wnt pathway contributes to PAH has not previously been studied. A team of researchers led by Vinicio de Jesus Perez, MD recently conducted a study to shed light on how the Wnt pathway influences PAH. Their results, co-first authored by Ananya Chakraborty PhD, Abinaya Nathan PhD, and Mark Orcholski, were recently reported in the European Respiratory Journal. They hypothesized that loss of Wnt activity in microvessel endothelial cells contributes to PAH - and they were right.

Microvessel cells from the lungs of healthy individuals had six fold higher Wnt7a expression during blood vessel growth compared to PAH cells. The investigators also found that Wnt7a was associated with the formation of special cells called ‘tip cells’ that migrate through the vascular tissue to help form new blood vessels. They showed that in PAH endothelial cells develop fewer tip cells. Further corroborating evidence that loss of Wnt7a contributes to PAH was demonstrated by showing that insertion of functional Wnt7a into PAH cells can rescue the deficits in tip formation and blood vessel repair activity.

Chakraborty, Nathan, Orcholski et al’s study is the first to uncover the role of Wnt7a in PAH. Ultimately, the investigators not only shed light on a specific signaling pathway that contributes to PAH, but also defined its mechanism of action: reduced Wnt7a signaling decreases the formation of tip cells that are important for repairing blood vessels.

Additional Stanford Cardiovascular Institute-affiliated investigators who contributed to this study include Stuti Agarwal, Natasha Auer, Ankita Mitra, Eleana Stephanie Guardado, Gowri Swaminathan, David F. Condon, Joyce Yu, Matthew McCarra, Nicholas H. Juul, Haley Hedlin, Jeffrey R. Fineman, Carsten N. F. Knutsen, Cristina M. Alvira, and David N. Cornfield.