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TRKB Signaling Promotes Alveolar Capillary Angiogenesis Following Perinatal Hyperoxic Damage

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE276575 | GEO | 2024/09/15

REPOSITORIES: GEO

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Project description:Background: Nrf2 is an essential cytoprotective transcription factor. However, association of Nrf2 in organ development and neonatal disease is rarely examined. Hyperoxia exposure to newborn rodents generates pulmonary phenotypes which resemble bronchopulmonary dysplasia (BPD) of prematurity. Methods: To investigate the role of Nrf2 in lung maturation and BPD pathogenesis, Nrf2-deficient (Nrf2-/-) and wild-type (Nrf2+/+) neonates were exposed to air or hyperoxia (O2). Transcriptome analysis determined Nrf2-directed mechanisms in premature lung. Lung injury was assessed by bronchoalveolar lavage analysis and histopathology. Results: In Nrf2-/- neonates, basal expression of cell cycle machinery, redox balance, and lipid/carbohydrate metabolism genes were suppressed while immunity genes were overexpressed compared to Nrf2+/+ pups. O2-induced mortality and pulmonary inflammation/injury were significantly higher in Nrf2-/- than in Nrf2+/+. Lung DNA lesion and oxidation were greater in Nrf2-/- than in Nrf2+/+, constitutively and after O2. Nrf2-dependent genes modulated cellular growth/proliferation, defense, immunity, and lipid metabolism against hyperoxia. Bioinformatic elucidation of Nrf2 binding motifs and augmented O2-induced inflammation in genetically deficient neonates validated Gpx2 and Marco as Nrf2 effectors. Conclusion: Overall, Nrf2 in underdeveloped lungs orchestrated cell cycle, morphogenesis, and immunity as well as cellular defense constitutively and under oxidant stress. Results provide putative molecular mechanisms of Nrf2-directed lung alveolarization and BPD of prematurity. PARALLEL study design with 42 samples comparing 14 groups of age (P1 to P4 corresponding to day 0 to day 3 animals), gene, and exposure: (4 groups Nrf+/+ wild type P1-P4 air exposure) (4 groups Nrf -/- knockout P1-P4 air exposure), (3 groups Nrf+/+ wild type P2-P4 with 100 percent O2 (hyperoxia exposure) and 3 groupsNrf -/- knockout P2-P4 with 100 percent O2 (hyperoxia exposure)) Biological replicates: 3 per group

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TRKB Signaling Promotes Alveolar Capillary Angiogenesis Following Perinatal Hyperoxic Damage

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