Liang-Ti Huang1, Hsiu-Chu Chou2, Chung-Ming Chen3. 1. Department of Pediatrics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. 2. Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. 3. Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan. Electronic address: cmchen@tmu.edu.tw.
Abstract
BACKGROUND: Premature infants who require oxygen therapy for respiratory distress syndrome often develop bronchopulmonary dysplasia, a chronic lung disease characterized by interrupted alveologenesis. Disrupted angiogenesis inhibits alveologenesis; however, the mechanisms through which disrupted angiogenesis affects lung development are poorly understood. Hypoxia-inducible factors (HIFs) are transcription factors that activate multiple oxygen-sensitive genes, including those encoding for vascular endothelial growth factor (VEGF). However, the HIF modulation of angiogenesis in hyperoxia-induced lung injury is not fully understood. Therefore, we explored the effects of roxadustat, an HIF stabilizer that has been shown to promote angiogenesis, in regulating pulmonary angiogenesis on hyperoxia exposure. METHODS: C57BL6 mice pups reared in room air and 85% O2 were injected with phosphate-buffered saline or 5 mg/kg or 10 mg/kg roxadustat. Their daily body weight and survival rate were recorded. Their lungs were excised for histology and angiogenic factor expression analyses on postnatal Day 7. RESULTS: Exposure to neonatal hyperoxia reduced body weight; survival rate; and expressions of von Willebrand factor, HIF-1α, phosphor mammalian target of rapamycin, VEGF, and endothelial nitric oxide synthase and increased the mean linear intercept values in the pups. Roxadustat administration reversed these effects. CONCLUSION: Hyperoxia suppressed pulmonary vascular development and the expression of proangiogenic factors. Roxadustat promoted pulmonary angiogenesis on hyperoxia exposure by stabilizing HIF-1α and upregulating the expression of proangiogenic factors, indicating its potential in clinical and therapeutic applications.
BACKGROUND: Premature infants who require oxygen therapy for respiratory distress syndrome often develop bronchopulmonary dysplasia, a chronic lung disease characterized by interrupted alveologenesis. Disrupted angiogenesis inhibits alveologenesis; however, the mechanisms through which disrupted angiogenesis affects lung development are poorly understood. Hypoxia-inducible factors (HIFs) are transcription factors that activate multiple oxygen-sensitive genes, including those encoding for vascular endothelial growth factor (VEGF). However, the HIF modulation of angiogenesis in hyperoxia-induced lung injury is not fully understood. Therefore, we explored the effects of roxadustat, an HIF stabilizer that has been shown to promote angiogenesis, in regulating pulmonary angiogenesis on hyperoxia exposure. METHODS: C57BL6 mice pups reared in room air and 85% O2 were injected with phosphate-buffered saline or 5 mg/kg or 10 mg/kg roxadustat. Their daily body weight and survival rate were recorded. Their lungs were excised for histology and angiogenic factor expression analyses on postnatal Day 7. RESULTS: Exposure to neonatal hyperoxia reduced body weight; survival rate; and expressions of von Willebrand factor, HIF-1α, phosphor mammalian target of rapamycin, VEGF, and endothelial nitric oxide synthase and increased the mean linear intercept values in the pups. Roxadustat administration reversed these effects. CONCLUSION: Hyperoxia suppressed pulmonary vascular development and the expression of proangiogenic factors. Roxadustat promoted pulmonary angiogenesis on hyperoxia exposure by stabilizing HIF-1α and upregulating the expression of proangiogenic factors, indicating its potential in clinical and therapeutic applications.
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