Multi-omics integration study of vascular smooth muscle cell phenotypic conversion identified novel biomarkers in idiopathic pulmonary arterial hypertension

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive, high‑mortality disease driven in part by maladaptive vascular remodeling. Phenotypic conversion of vascular smooth muscle cells (VSMCs) is implicated in this process, but the cellular heterogeneity and regulatory drivers in IPAH remain incompletely defined. METHODS: We integrated scRNA‑seq datasets from IPAH and control lungs samples with bulk RNA‑seq from IPAH patients, MCT‑induced rat IPAH models, applying diffusion‑map dimensionality reduction, pseudotime inference, CellChat, and machine learning to nominate phenotypic conversion regulatory genes (PCRGs). Candidate genes were validated in independent cohorts and functionally tested in hypoxia‑induced human PASMCs. RESULTS: Single-cell analysis identified three VSMC clusters-contractile, proliferative, and synthetic-and reconstructed a dedifferentiation trajectory. 40 PCRGs correlated with the primary diffusion-map component, of which POSTN and CCDC80 emerged as hub genes up-regulated in rat and human IPAH cohorts. Hypoxia induced their expression in PASMCs, and siRNA knockdown attenuated hypoxia‑driven proliferation and migration. A multivariable VSMC phenotypic conversion signature (VPCS) integrating these biomarkers and clinical variables demonstrated robust diagnostic discrimination in validation datasets. CONCLUSIONS: Our from high‑dimensional datasets.integrative VSMC‑centered approach delineates dynamic state transitions in IPAH, nominates CCDC80 and POSTN as candidate regulators and biomarkers, and offers a practical framework for prioritizing targets