EBF1 specifies a transient embryonic endothelial niche population that organizes pulmonary artery morphogenesis through vasculotrophic signaling to coordinate progenitor proliferation, arterial differentiation, and stromal maturation; this developmental niche is aberrantly reactivated in pulmonary arterial hypertension where EBF1+ endothelial cells regenerate from general capillary stem cells to drive pathological vascular remodeling through maladaptive recapitulation of their developmental organizing function.

Developmental mechanisms that precisely orchestrate cell fate and tissue architecture in organogenesis can be aberrantly reactivated to cause disease. Here we identify a previously uncharacterized population of endothelial niche cells, defined by the pioneer factor early B cell factor 1 (EBF1), that promotes both the development and pathological remodeling of pulmonary arteries (PAs). We show in the embryonic lung that the PA arises from an endothelial niche harbored within the vascular plexus, regulating Aplnr+ progenitors that differentiate into arterial endothelial cells (ECs) and Ebf1+ ECs. Instead of directly incorporating into the PA endothelium, these Ebf1+ ECs secrete vasculotrophic signals that organize the proper expansion and arterialization of plexus progenitors with the recruitment of the mesenchymal cells that muscularize and ensheathe the maturing PA. Although essential in development, most Ebf1+ ECs disappear by completion of PA morphogenesis. In adult PAH, the embryonic artery-forming niche is reactivated. The normally quiescent Aplnr+ general capillary stem cells re-enter the cell cycle and regenerate arterial ECs and Ebf1+ ECs. By expressing key vasculotrophic signals including Apelin, Cxcl12/Cxcr4, Notch, and Tgf-β, these Ebf1+ ECs promote angiogenesis, neo- arterialization, and neo-muscularization in a maladaptive process echoing their role in development. Our findings define a novel developmental mechanism featuring unusually transient PA organizing cells. We suggest their reemergence in adulthood drives vascular pathology and that targeting these Ebf1+ ECs could halt or reverse PAH.