Abstract
Pulmonary capillary endothelial cells (ECs) consist of two populations, CAP1 and CAP2; how each population reacts to diverse tissue injury is incompletely understood. Using single-cell multiome and mouse genetics, we characterize the induction and function of a truncated isoform of Ntrk2, Ntrk2-T1, in multiple lung injury models. Upon Sendai parainfluenza infection, Ntrk2-T1 is broadly induced in CAP1s after the initial interferon response, associated with increased intronic chromatin accessibility, and persists for weeks. Ntrk2-T1 ECs arise from CAP1s but not CAP2s-traced by Kit CreER and Car4 CreER , respectively-and proliferate and give rise to CAP1s but not CAP2s, as traced by Ntrk2 CreER . Although also induced by lipopolysaccharide, H3N2 influenza, and COVID-19 injuries, EC-specific deletion of Ntrk2 has limited molecular and cellular consequences. Individuals with incident and prevalent respiratory diseases have lower plasma NTRK2. Our data identifies Ntrk2-T1 as an EC marker of lung injury-repair and enhances our understanding of EC heterogeneity.