Vascular Progenitor Cells’ Receptor Protein May Be New PAH Target

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A receptor protein at the surface of lung vascular progenitor cells regulates the cells’ growth and maturation into smooth muscle cells, contributing to the vascular remodeling that characterizes pulmonary arterial hypertension (PAH), a study shows.

Suppressing this protein — called platelet-derived growth factor receptor alpha (PDGFR-alpha) — prevents these progenitor cells from being recruited and pulmonary vascular remodeling in a mouse model of chronic hypoxia-induced pulmonary hypertension (PH). Hypoxia refers to low oxygen conditions and chronic hypoxia is a common cause of PH.

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

The study, “Platelet‐Derived Growth Factor Receptor Type α Activation Drives Pulmonary Vascular Remodeling Via Progenitor Cell Proliferation and Induces Pulmonary Hypertension,” was published in the Journal of the American Heart Association.

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

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Arterial narrowing is the result of excessive blood vessel contraction and remodeling, a process that involves the uncontrolled growth of smooth muscle cells (SMCs), progressively thickening the arterial walls.

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

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

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

The research team, along with colleagues in Australia, evaluated the role of PDGFR-alpha in progenitor cell‐dependent vascular remodeling and in PH development.

A cell surface receptor protein, PDGFR-alpha belongs to the platelet‐derived growth factor (PDGF) pathway, which has been suggested “as a major regulator of pulmonary vascular remodeling and PAH development,” the researchers wrote.

Both PDGF’s ligands (binding molecules) and receptors were previously shown to be at significantly higher levels in PAH patients’ lungs relative to healthy people, but most research to date has focused on only one of the two receptors of PDGF — PDGFR-beta.

Notably, 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 looking at lung tissue from five PAH patients and five healthy people, the researchers found that PW1/PDGFR-alpha-positive vascular progenitor cells accumulated around blood vessels in PAH patients. The samples also showed a significantly higher number of progenitor cells containing alpha smooth muscle actin (alpha-SMA), a marker of 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, an anti-cancer medication, 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 with either approach prevented the chronic hypoxia-induced recruitment, growth, and maturation of progenitor cells into SMCs, and significantly reduced lung vessel neomuscularization.

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

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

As such, mice with induced PDGFR-alpha activation may represent a “novel mouse model of mild pulmonary hypertension in males, recapitulating the pulmonary vascular alterations observed during chronic hypoxia,” the researchers wrote.

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

These findings highlight PDGFR-alpha “as an essential regulator of lung vessel neomuscularization via the recruitment of vascular progenitor cells and opens new avenues for pulmonary hypertension medication,” they wrote. “A multitarget therapeutic strategy associating [PDGFR-alpha blocking] with current vasodilating therapies may provide beneficial effects by inhibiting progenitor cell recruitment and vessel neomuscularization.”