Exploring the Impact of Platelet‐Derived Growth Factor D in Pulmonary Hypertension Development

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ABSTRACT Pulmonary arterial hypertension (PAH) is a life‐threatening condition with no cure, making research into its underlying mechanisms critical. The platelet‐derived growth factor (PDGF) signaling pathway plays a crucial role in vascular remodeling, a key factor in PAH progression. Anti‐PDGF receptor therapies, such as imatinib, show promise but are associated with significant side effects. Recent research identified PDGF‐D as a new risk gene in idiopathic PAH, highlighting the need for further investigation into the PDGF pathway in the disease. In this study, we investigated PDGF‐D, a specific PDGFRβ ligand, as a potential therapeutic target. RNA‐Seq data from healthy lungs indicated that PDGF‐D is predominantly expressed in inflammatory cells, whereas in vascular lesions of idiopathic PAH patients, PDGF‐D was produced by various cell types. In vitro, PDGF‐D induced mitogenic effects on pulmonary arterial smooth muscle cells. However, genetic deletion of PDGF‐D in the chronic hypoxia mouse model of pulmonary hypertension showed no significant impact on vascular muscularization, hemodynamic parameters, or right ventricular hypertrophy. But, the absence of hypoxia‐induced Pdgfrb upregulation and the lack of increased expression of PAH‐regulated genes, Fgf2 and Notch3 , in PDGF‐D‐deficient mice, suggests activation of alternative mechanisms. MicroRNA analyses revealed PDGF‐ D ‐related alterations in the expression of miR‐21 and miR‐451, both important regulators in PAH, further supporting the notion that PDGF‐D plays a unique role in PAH development. Taken together, our data suggest that PDGF‐D may target a distinct population of PDGFRβ‐expressing cells, separate from those stimulated by PDGF‐B, positioning PDGF‐D as a potentially unique and compelling therapeutic target for PAH.

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