IPSC‐Derived Conditioned Medium Reduces Oxidative Stress and Vascular Remodeling in Rat Models of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by elevated pulmonary vascular resistance, leading to right ventricular (RV) hypertrophy and eventual heart failure. Although current therapies provide symptomatic relief, they offer limited efficacy in reversing the underlying vascular remodeling. In this preclinical study, we investigated the therapeutic potential of induced pluripotent stem cell-derived conditioned medium (iPSC-CM) in a monocrotaline (MCT)-induced rat model of PAH, employing both prophylactic and therapeutic administration strategies. iPSC-CM treatment significantly reduced right ventricular systolic pressure (RVSP) and mitigated RV hypertrophy compared to MCT-only controls. Histological analyses revealed attenuated pulmonary arterial wall thickening and muscularization. At the molecular level, iPSC-CM downregulated the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and platelet-derived growth factor-BB (PDGF-BB) in lung tissues, and modulated oxidative stress by decreasing NADPH oxidase 1 (Nox1) and increasing superoxide dismutase 1 (SOD1) levels. In vitro, iPSC-CM suppressed the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) under hypoxic and PDGF-BB-stimulated conditions. These findings suggest that iPSC-CM targets key pathogenic pathways involved in vascular remodeling and redox imbalance in PAH. Together, these findings support iPSC-CM as a promising acellular approach for targeting vascular remodeling and oxidative stress in PAH, warranting further investigation toward clinical translation.