The Role of Vitamin D in Pulmonary Arterial Hypertension: From Vascular Biology to Patient Outcomes.

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease characterized by endothelial dysfunction, excessive vasoconstriction, vascular remodeling, and right ventricular failure. In recent years, vitamin D (VitD) has emerged as a potential modulator of several biological pathways implicated in PAH pathobiology. Beyond its classical role in calcium and phosphate homeostasis, VitD exerts pleiotropic effects through activation of the VitD receptor, which is expressed in pulmonary artery endothelial cells and smooth muscle cells. Experimental evidence indicates that VitD signaling is associated with the regulation of key mechanisms involved in PAH, including endothelial nitric oxide production, prostacyclin and endothelin pathways, Endothelial-to-Mesenchymal Transition, smooth muscle cell proliferation, inflammation, oxidative stress, mitochondrial dysfunction, and extracellular matrix remodeling. Studies conducted in experimental pulmonary hypertension models, including models with PAH-like vascular remodeling, have reported associations between VitD restoration and improved pulmonary hemodynamics, right ventricular function, endothelial function, and pulmonary vascular remodeling. However, these models do not fully recapitulate human Group 1 PAH and therefore their findings should be interpreted cautiously. Clinical studies have demonstrated a high prevalence of VitD deficiency among patients with PAH, although several studies have included heterogeneous PH populations, and lower circulating 25-hydroxyvitamin D levels have been associated with worse functional class, reduced exercise capacity, more severe hemodynamic impairment, right ventricular dysfunction, and poorer survival. However, clinical evidence regarding the benefits of VitD supplementation remains limited and is mainly derived from small observational studies and uncontrolled interventions. This narrative review summarizes the current experimental and clinical evidence linking VitD to PAH pathobiology and patient outcomes, highlighting potential mechanistic pathways and discussing the opportunities and challenges for future therapeutic strategies. Although available data support a biologically plausible association between VitD/VitD receptor signaling and pulmonary vascular homeostasis, adequately powered randomized controlled trials are required to determine whether correction of VitD deficiency is associated with improved clinical outcomes in PAH.