microRNA-708及其调控Notch信号通路介导的血管生成在新生儿支气管肺发育不良中的机制研究

Bronchopulmonary dysplasia (BPD)，the risk factor for the chronic respiratory diseases of infancy，is a chronic lung disease in perinatal period.Angiogenesis is the key process in alveolar development, however，abnormal angiogenesis results in BPD. We have found that hyperoxia can significantly decrease the expression of microRNA-708 and increase the expression of Notch1 in pulmonary endothelial cells, and transfection of HMVEC cells with microRNA-708 significantly inhibited Notch1 expression at protein level in HMVEC cells. These results indicate that microRNA-708-mediated Notch signaling pathway might be involved in regulation of the neonatal pulmonary angiogenesis. The current study is to elucidate the expression changes of microRNA-708 in pulmonary endothelial cells during fetal and perinatal period in the mouse model.It will illuminate the regulation mechanism of microRNA-708 expression under conditions of hyperoxia, and the effects of the Notch signaling pathway on hyperoxia-induced endothelia dysfunction and angiogenesis in vitro and in neonatal mouse model of hyperoxia. To evaluate the role of microRNA-708 in the pathogenesis of hyperoxia-induced lung injury in newborns will provide new insight into the treatment of BPD.

支气管肺发育不良（bronchopulmonary dysplasia，BPD）是一种围产期婴儿慢性肺疾病，是婴儿期慢性呼吸系统疾病的主要病因。血管生成是正常肺泡发育的关键，异常血管生成可导致BPD。我们已证实高氧暴露肺血管内皮细胞HMVEC中MicroRNA-708表达显著降低而Notch1表达显著增高，且microRNA-708可抑制Notch1蛋白表达。推测MicroRNA-708通过Notch信号通路参与了新生儿肺血管生成的调控。本课题拟通过小鼠动物模型研究胚胎发育及围产期肺血管内皮细胞MicroRNA-708的表达模式；通过体外细胞学实验和高氧小鼠动物模型研究在高氧条件下MicroRNA-708的表达调控机制；以及其调控的Notch信号通路对高氧诱导的内皮功能紊乱和血管生成的影响。阐明microRNA-708在新生儿高氧肺损伤机制中作用，为BPD治疗提供新的思路和治疗手段。

支气管肺发育不良是一种围产期婴儿慢性肺疾病，是婴儿期慢性呼吸系统疾病的主要病因。血管生成是正常肺泡发育的关键，异常血管生成可导致BPD。我们发现高氧暴露肺血管内皮细胞HMVEC中MicroRNA-708表达显著降低而Notch1表达显著增高，且microRNA-708可抑制Notch1蛋白表达，且Notch1 3’UTR存在MicroRNA-708的结合位点。进一步的研究发现，高氧处理下microRNA-708过表达可提高肺血管完整性并缓解高氧所致的肺损伤。体外实验结果表明，microRNA-708过表达可提高HMVEC细胞抗氧化能力及其细胞增殖活性，并促进HMVEC细胞迁移和血管生成。以上结果提示，microRNA-708通过调控Notch1的表达参与血管内皮细胞迁移和血管生成，同时通过提高血管内皮细胞的抗氧化能力及其细胞增殖活性在高氧条件下提高肺血管完整性以缓解高氧所致的肺损伤。