Rebalancing NTRK2 isoforms promotes vascular regeneration in bronchopulmonary dysplasia.

Abstract

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity with no curative therapy, characterized by impaired alveologenesis and capillary formation. However, the molecular mechanisms underlying endothelial dysfunction, a key driver of BPD pathogenesis, remain poorly understood. Through multiomic profiling of endothelial cells isolated from human BPD lungs, we identified an expansion of general capillary endothelial cells (gCaps) marked by neurotrophic receptor tyrosine kinase 2 (NTRK2). Notably, we uncovered a critical isoform switch that governs gCap regeneration. Full-length NTRK2 (NTRK2-FL) promoted gCap repair after hyperoxic injury, whereas RBFOX2-mediated splicing of NTRK2-FL into a truncated isoform (NTRK2-T1) contributed to maladaptive responses and persistent alveolar simplification. Restoring NTRK2-FL using lipid nanoparticle-delivered mRNA promoted angiogenesis in vessel organoids and reversed alveolar simplification in hyperoxic mice. These findings identified NTRK2 isoform imbalance as a key driver of endothelial dysfunction and support isoform-specific RNA therapy as a promising strategy for vascular regeneration and repair.