Targeting HIF-2alpha protein may be therapeutic approach for PAH

Protein plays role in response to low oxygen conditions

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by Andrea Lobo |

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An oversized human hand holds a mouse in a laboratory, alongside a rack with a trio of filled vials.

Findings of a new study into pericytes — cells with multiple functions including immune cell regulation — suggest that targeting a protein known as HIF-2alpha, which is involved in the response to low oxygen conditions, or hypoxia, may be a potential therapeutic approach for pulmonary arterial hypertension (PAH).

The study found that HIF-2alpha regulates the transformation of pericytes into smooth muscle-like cells, contributing to blood vessel changes that characterize PAH. Pericytes, which wrap around blood vessel walls, regulate immune cell entry to the brain and control blood flow, among other functions.

According to Ke Yuan, PhD, a researcher at Boston Children’s Hospital and senior author of the study, “pericytes are abundant all over the body, but they’ve never been studied for their role in pulmonary or cardiovascular diseases.”

“They’ve been overlooked, but our work suggests they contribute to the vascular remodeling process behind pulmonary hypertension and other cardiovascular diseases,” Yuan said in a press release.

The study, “Pericytes contribute to pulmonary vascular remodeling via HIF2[alpha] signaling,” was published in EMBO Reports.

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Studying PAH mechanisms to find a new therapeutic approach

PAH is caused by the narrowing of pulmonary arteries — blood vessels that transport blood through the lungs — that restricts blood flow, causing high blood pressure and making the heart’s right ventricle work harder to pump blood.

Remodeling of arterial walls, involving an uncontrolled growth of smooth muscle cells (SMCs), is associated with these changes. Many studies have focused on the effects of vascular endothelial cells and SMCs during vascular remodeling, but pericytes have largely been ignored.

In this study, the researchers wanted to understand whether pericytes exposed to hypoxia could participate in vascular remodeling that results in PAH.

To start, the team analyzed changes in the expression, or activity, of genes in lungs, based on previously published datasets comparing patients with idiopathic (no known cause) PAH with controls. The results showed the existence of 27 cell clusters based on the patterns of genes they expressed.

One of the clusters was named a pericyte cluster, based on its high expression of the EPAS1 gene in most cells. EPAS1 gene encodes the HIF-2alpha protein, which was found at higher levels in pericytes derived from patients as compared with the controls.

In further experiments, the scientists found that pericytes engineered to express increased levels of HIF-2alpha transformed into SMC-like cells under hypoxia. The study also found high HIF-2alpha levels in a mouse model of hypoxia, and further, that selective increases of HIF-2alpha in pericytes exacerbated PH and right ventricle enlargement. Conversely, deletion of HIF-2alpha in pericytes eased the remodeling of small arteries.

When the researchers traced the origin of newly formed SMCs, they found that pericytes with high levels of HIF-2alpha become SMC-like cells during vascular remodeling. Finally, blocking HIF-2alpha’s signaling with a compound known as AMD3100 — known to prevent increases of muscle tissue in pulmonary arteries in animal models of PH — protected mice from hypoxia-induced pulmonary hypertension.

Overall, “[HIF-2alpha] signaling plays an important role in the transition of pericytes into smooth muscle cell-like cells in pulmonary hypertension. Hence, targeting [HIF-2alpha] in pericytes may be a potential therapeutic approach for pulmonary hypertension,” the researchers concluded.

Yuan said the ultimate goal is to find new treatments for PAH.

“If we find out how pericytes change lineage and are associated with pulmonary hypertension, we want to design therapies to prevent them from becoming smooth muscle-like cells,” Yuan said.

In next steps, the team intends to learn more about how pericytes contribute to blood vessel remodeling in PAH. With that knowledge, the researchers would seek to develop better tools to distinguish pericytes from SMCs, and investigate how pericytes contribute to the enlargement of the heart’s right ventricle.

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