Li-Wei Wu, Min Chen, Chen-Yu Jiang, Dai-Ji Jiang, Xu Zhang, Xiao-He Xu, Yi-Wei Liu, Bei Feng, Lin-Cai Ye, Yang-Yang He, Xu Huang, Yi-Chi Zhang, Xing-Liang Zhou, Yi Shen, Tian-Yu Liu, Li-Jun Fu, Yi Yan, Hao Zhang
Shanghai Children’s Medical Center, National Children’s Medical Center and Shanghai Jiao Tong University School of Medicine. Second Affiliated Hospital and Yuying Children’s Hospital and Wenzhou Medical University. Henan University.
China
Advanced Science
Adv Sci 2025;
DOI: 10.1002/advs.202508995
Abstract
Right ventricular (RV) adaptation critically determines survival in pulmonary hypertension (PH). Since cardiac fibroblasts (FBs) are crucial mediators of cardiac fibrosis, we aim to uncover the mechanism underlying their activation during RV remodeling. Using single-nucleus RNA sequencing (snRNA-seq) across three rodent PH models-hypobaric hypoxia and Sugen 5416/hypoxia in mice, and monocrotaline in rats-we identified elevated Axl expression in RV FBs under PH. AXL upregulation was consistently observed in RV FBs from both human PH patients and animal models. Cardiac FB-specific Axl overexpression exacerbated RV remodeling in both PH and pulmonary artery banding (PAB) models, whereas Axl knockdown in FBs alleviated this remodeling. Functionally, AXL promoted FB proliferation, migration, and extracellular matrix synthesis via the PI3K-AKT pathway, facilitating nuclear translocation of NFIC, which in turn promoted the transcription of targeted genes such as COL1A1. Inhibiting PI3K or administering R428 mitigated AXL-driven RV remodeling in PH, and R428 also ameliorated remodeling in PAB mice. In conclusion, AXL signals the PI3K-AKT pathway to license nuclear translocation of NFIC, thereby dictating the transcription of fibrotic genes in FBs and driving RV remodeling. These findings reveal novel insights into RV pathophysiology and highlight AXL as a potential therapeutic target for PH-induced RV remodeling.
Category
Heart Dysfunction Associated with Pulmonary Vascular Disease (Right)
Animal Models of Pulmonary Vascular Disease and Therapy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes