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 Ntrk2, 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 further promoting pulmonary angiogenesis using the hyperoxia mouse BPD model. TRKB activation by 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 capillary 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 might act downstream of TRKB to modulate pulmonary angiogenesis. These data indicate that TRKB signaling play 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. Overall design: We performed RNA-seq on MACS-sorted CD31+ lung endothelial cells isolated from mice maintained in room air (RA, 21% oxygen) or hyperoxia (HO, 75% oxygen). Mice were subjected to treatment on postnatal day 0, and lungs were harvested on postnatal day 7.