TrkB signaling promotes alveolar capillary angiogenesis following perinatal hyperoxic damage

Impaired angiogenesis characterized by the reduced proliferation of pulmonary endothelial cells leads to reduced capillary density in patients with bronchopulmonary dysplasia (BPD). In a mouse model of BPD, perinatal hyperoxic injury decreases the number of the recently identified lung capillary stem cells termed as general capillary (gCap) cells, along with the specific reduction of <i>Ntrk2</i>, which encodes for tropomyosin receptor kinase B (TrkB), within this subpopulation. Herein, we determine whether TrkB signaling is required for perinatal gCap cell proliferation and pulmonary angiogenesis in a hyperoxia mouse BPD model. TrkB activation by brain-derived neurotrophic factor (BDNF) treatment led to enhanced tube-forming ability of endothelial cells in vitro. In vivo treatment of mice with BDNF increased the proliferation of gCap cells and alleviated gCap loss caused by hyperoxic injury. Conversely, inhibition of TrkB signaling disrupted the tube formation of endothelial cells and exaggerated the vascular endothelial damage caused by hyperoxia. We further show that MAPK/ERK signaling acts downstream of TrkB to modulate pulmonary angiogenesis. These data indicate that TrkB signaling plays a critical role in pulmonary angiogenesis upon perinatal lung injury, supporting the concept that TrkB activation might be a potential therapeutic for preserving endothelial cells for lung diseases associated with prematurity.<b>NEW & NOTEWORTHY</b> The present study highlights the essential role of BDNF/TrkB signaling in capillary endothelial cell proliferation and preserving alveolar architecture during perinatal hyperoxic lung injury, supporting the concept that activation of TrkB/MAPK/ERK signaling might be a strategy to restore alveolar angiogenesis for preterm infants at risk of BPD.