An embryonic artery-forming niche 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 directly incorporating 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. In adult PAH, vascular injury reactivates this developmental program: normally quiescent general capillary ECs re-enter the cell cycle and differentiate into arterial ECs and EBF1+ ECs, reconstituting this artery-forming niche in a maladaptive reprise. Unlike their transient embryonic counterparts, EBF1+ ECs persist within neointimal lesions and express vasculotrophic signals associated with pathological PA remodeling. Capillary-restricted Ebf1 induction combined with endothelial injury recapitulates this program, driving neo-arterialization, neointimal formation, and severe PAH. Conversely, endothelial-targeted AAV-mediated Ebf1 knockdown achieves complete protection in a preclinical model of disease, demonstrating that endothelial EBF1 is necessary for PAH pathogenesis. These findings demonstrate that reactivation and persistence of a transient embryonic artery-forming niche in adulthood can promote pathological vascular remodeling and PAH.