Suppressing the receptor protein helps prevent PAH development in mice

A study shows that a receptor protein on the surface of pulmonary vascular progenitor cells regulates the growth and maturation of cells into smooth muscle cells and contributes to the vascular remodeling characteristic of pulmonary arterial hypertension (PAH).

Suppression of this protein – called platelet growth factor receptor alpha (PDGFR-alpha) – prevents recruitment of these progenitor cells and remodeling of the pulmonary vessels in a mouse model of chronic hypoxia-induced pulmonary hypertension (PH). Hypoxia refers to conditions of low oxygen levels, and chronic hypoxia is a common cause of PH.

These results suggest that blocking PDGFR-alpha could be a new therapeutic approach to reduce vascular remodeling in people with PAH, the researchers noted.

The study, “Activation of platelet growth factor receptor type α drives pulmonary vascular remodeling via progenitor cell proliferation and induces pulmonary hypertension“, was published in Journal of the American Heart Association.

In PAH, the endothelial cells — the cells that line blood vessels — are impaired and the pulmonary arteries narrow, restricting the flow of blood and oxygen and increasing blood pressure (hypertension).

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Narrowing of the arteries is the result of excessive contraction and remodeling of blood vessels, a process that involves the uncontrolled growth of smooth muscle cells (SMCs) and progressively thickens artery walls.

This process, known as neomuscularization, is driven by both SMC growth and recruitment of SMC progenitor cells.

In a previous study, a team of researchers in France showed that a population of pulmonary vascular progenitor cells – characterized by the presence of the stem cell markers PW1 and PDGFR-alpha – are involved in early pulmonary vascular neomuscularization during PAH.

However, “the specific factors affecting their [growth] remained unknown,” the researchers wrote.

The research team, together with colleagues in Australia, assessed the role of PDGFR-alpha in progenitor-dependent vascular remodeling and PH development.

PDGFR-alpha, a cell surface receptor protein, is part of the platelet growth factor (PDGF) signaling pathway, which has been “proposed to be a master regulator of pulmonary vascular remodeling and PAH development,” the researchers wrote.

Both the ligands (binding molecules) and receptors of PDGF have previously been found at significantly higher levels in the lungs of PAH patients compared to healthy people, but most research to date has focused on just one of PDGF’s two receptors – PDGFR -beta.

In particular, PDGFR-alpha and its ligand PDGF-A have been shown to regulate stem cell growth and maturation, suggesting that a similar role may occur in pulmonary vascular progenitor cells.

By examining lung tissue from five PAH patients and five healthy people, the researchers found that PW1/PDGFR-alpha-positive vascular progenitor cells accumulated around the blood vessels of PAH patients. The samples also showed a significantly higher number of progenitor cells containing alpha-smooth muscle actin (alpha-SMA), a marker for SMCs.

The team then analyzed the effects of suppressing PDGFR-alpha in a mouse model of chronic hypoxia-induced PH by treating the mice with either imatinib or APA5.

Imatinib, a cancer drug, is known to block the activity of molecules such as PDGFRs and has been evaluated in PH models and PAH patients. APA5 is an antibody that specifically targets PDGFR-alpha.

Results showed that blocking PDGFR-alpha in both approaches prevented chronic hypoxia-induced recruitment, growth and maturation of progenitor cells into SMCs and significantly reduced pulmonary vessel neomuscularization.

Remarkably, neomuscularization was only partially suppressed, “suggesting that pathways other than PDGF also regulate the production of new SMCs,” the researchers wrote.

The researchers showed that activation of the PDGFR-alpha signaling pathway promoted neomuscularization via the growth and maturation of PW1-positive progenitor cells into new SMCs and led to the development of mild PH in male mice.

Therefore, mice with induced PDGFR-alpha activation may represent a “novel mouse model of mild male pulmonary hypertension that recapitulates the pulmonary vascular changes observed during chronic hypoxia,” the researchers wrote.

More studies are needed to understand the mechanisms leading to increased lung pressure in this model, the researchers noted.

These results underscore PDGFR-alpha “as a key regulator of pulmonary vascular neomuscularization through recruitment of vascular progenitor cells and open new avenues for drugs to treat pulmonary hypertension,” they wrote. “An associative therapeutic strategy for multiple targets [PDGFR-alpha blocking] with current vasodilator therapies can produce beneficial effects by inhibiting progenitor cell recruitment and vascular neomuscularization.”

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