SnRNA-seq identifies FN1-SDC4 axis triggering epicardial activation in right ventricular remodeling in pulmonary hypertension

Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by pulmonary vascular remodeling, ultimately leading to right heart failure. In this study, a murine model of PH was established by exposing mice to chronic hypoxia for four weeks. Compared with normoxic controls, PH mice exhibited significantly elevated right ventricular systolic pressure and pronounced right ventricular (RV) remodeling. Single-nucleus RNA sequencing (snRNA-seq) was subsequently performed to characterize molecular changes in the RV secondary to PH. Cell communication analysis revealed Fn1-related signaling pathways in PH RV. This finding was further corroborated by consistent upregulation of Fn1 and its receptor Sdc4 in both human and rodent PH RV transcriptomic datasets. In murine PH RV, the proportion of Sdc4-expressing epicardial cells was notably increased. Pseudotime trajectory analysis further identified a distinct epicardial cell subpopulation (cluster 1), highly associated with PH progression, that was enriched in biological processes including cell growth and extracellular matrix (ECM)-receptor interactions. Functionally, Fn1 promotes epicardial cell proliferation and epithelial-mesenchymal transition (EMT) in a Sdc4-dependent manner. Crucially, epicardial cell specific Sdc4 knockdown ameliorated RV remodeling in PH models. Taken together, these findings elucidate the role of the Fn1-Sdc4 axis in RV remodeling and suggest its potential as a therapeutic target for mitigating RV dysfunction in PH.