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

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 <i>Pdgfrb</i> upregulation and the lack of increased expression of PAH-regulated genes, <i>Fgf2</i> and <i>Notch3</i>, 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.