EBF1 controls an embryonic artery-forming niche that reactivates in pulmonary arterial hypertension

Abstract

Developmental programs that orchestrate cell fate and tissue architecture during organogenesis can cause disease when reactivated in adults. Here we identify a population of endothelial cells (ECs) defined by the pioneer factor early B cell factor 1 (EBF1) that controls both pulmonary artery (PA) morphogenesis and pulmonary arterial hypertension (PAH). During embryonic development, the PA emerges from an endothelial niche harbored within the vascular plexus, where Aplnr+ endothelial progenitors give rise to both arterial ECs and EBF1+ ECs. Rather than incorporating directly into the PA intima, EBF1+ ECs control the branching and maturation of the PA tree through paracrine vasculotrophic signals that direct plexus expansion, arterialization, and mural cell recruitment. Although essential for development, most EBF1+ ECs disappear upon completion of PA morphogenesis, leaving only a rare residual population within the adult Aplnr+ gCap compartment. In PAH, vascular injury reactivates the EBF1 program through recruitment of the pre-existing Ebf1 lineage together with an additional contribution consistent with de novo Ebf1 induction in gCaps, reconstituting this artery-forming niche in a maladaptive reprise of PA development. Unlike their transient embryonic counterparts, these EBF1+ ECs persist within occlusive intimal lesions and express vasculotrophic signals associated with pathological PA remodeling. Combined with endothelial injury, gCap-specific Ebf1 overexpression drives a coordinated program of neo-arterialization, occlusive vascular remodeling, and severe PAH. Conversely, gCap-specific genetic deletion of Ebf1 in mice and endothelial-targeted AAV-mediated Ebf1 knockdown in rats protect against disease, showing that endothelial EBF1 is required for PAH pathogenesis. These findings demonstrate that reactivation and persistence of a transient embryonic artery-forming niche in adulthood drive pathological vascular remodeling and PAH.