Abstract Pulmonary arterial hypertension (PAH) is a severe, progressive, and ultimately incurable lung vascular disease in which endothelial dysfunction is a central pathological hallmark. Although multiple molecular mechanisms contributing to PAH have been described, the epigenetic drivers that promote abnormal endothelial remodeling and PAH remain poorly understood. We investigated the role of the epigenetic regulator Tet methylcytosine dioxygenase 2 (Tet2) in lung endothelial homeostasis and injury using an inducible, endothelial-specific Tet2 knockout mouse line (Cdh5-CreERT2;Tet2fl/fl, Tet2ECiKO). Unexpectedly, tamoxifen-induced deletion of Tet2 in endothelial cells led to the spontaneous development of severe PAH by 6 months of age, with right ventricular systolic pressure (RVSP) exceeding 40 mm Hg and pronounced muscularization and remodeling of distal pulmonary microvessels. Lineage-tracing analysis revealed dysregulated phenotypic transitions of capillary endothelial cells that contributed to pathological pulmonary vascular remodeling in Tet2ECiKO mice. These findings identify endothelial Tet2-dependent epigenetic regulation as a critical brake on spontaneous pulmonary vascular remodeling and suggest that targeting endothelial epigenetic pathways may represent a novel therapeutic strategy for PAH. In addition, the Tet2ECiKO mouse provides a new inducible preclinical model for studying PAH pathogenesis. This research was supported by NIH/NHLBI R01HL176717 and R01HL169447 (to B.Z.). This abstract is funded by: NIH
Zhou et al. (Fri,) studied this question.