脂肪细胞外泌体来源的NOX4诱导肥胖妊娠胎盘早衰的机制研究

Obese pregnancy with high risks of adverse outcomes and limiting of intervention strategies challenges women health in childbearing ages, which pathogenetic mechanism is still unknown. Our preliminary data demonstrated high level of ROS and cell senescence in placenta of obese pregnancy, which indicating oxidative stress induced placenta premature senescence might be important pathologic basis of adverse outcomes in obese pregnancy. Protein NOX4, mainly expressed in adipocyte, is a key regulator of ROS generation. We found that protein NOX4 was significantly high expressed in placenta of obese pregnancy. However, its level of mRNA was similar to normal placenta. Besides, we also found that fat adipocyte-derived exosomes were rich in NOX4 protein and could be uptaked by trophoblasts demonstrated by vitro experiments. Therefore, this study proposes that fat adipocyte-derived exosomal NOX4 can be uptaked by trophoblasts causing ROS level increased and thus be an important contributor to induce placenta premature senescence. In this study, we will focus on protein NOX4 derived from adipocyte and investgate the mechanism of exosomal NOX4 induced trophoblasts senescence, with expect to provide novel strategy and experimental evidence for improving placental premature senescence in obese pregnancy.

肥胖妊娠不良结局发生率显著升高，其发生机制尚不明确，且孕期干预手段有限，严重挑战育龄期妇女妊娠健康。课题组前期发现肥胖妊娠胎盘组织ROS水平及细胞衰老水平显著升高，提示氧化应激所致胎盘早衰可能是肥胖不良妊娠结局发生的重要病理基础。NOX4蛋白主要表达于脂肪组织，是介导ROS生成的重要因子。课题组发现肥胖妊娠胎盘组织中NOX4蛋白的表达显著升高，mRNA水平却与正常胎盘组织无明显差异；肥胖脂肪细胞来源的外泌体中含有丰富的NOX4蛋白，体外实验表明滋养细胞可摄取脂肪细胞来源的外泌体。因此，课题组推测肥胖脂肪细胞外泌体来源的NOX4，可被滋养细胞摄取，引起胞内ROS水平升高，是诱导细胞衰老促进胎盘早衰的重要原因之一。本项目拟以脂肪细胞NOX4为研究对象，深入探讨NOX4经外泌体诱导滋养细胞衰老的分子机制，有望为改善肥胖妊娠胎盘早衰提供新的思路和实验证据。

近年来，母体肥胖率不断上升，母体肥胖与母胎并发症、胎盘功能障碍和不良妊娠结局有关，这可能是由于氧化损伤增加导致胎盘过早衰老所致。肥胖时脂肪组织通常会释放过量的活性氧和促炎细胞因子。NADPH氧化酶4 (NOX4)在脂肪组织中大量表达，可能是肥胖时胎盘中ROS的主要来源。但NOX4与胎盘的直接联系尚不清楚。外泌体在脂肪组织和胎盘之间的交流中起着重要作用。因此，在本研究中，我们推测脂肪组织来源的NOX4通过外泌体诱导胎盘氧化损伤和早衰老。本研究从肥胖和正常妊娠中采集足月胎盘组织，通过高脂饮食建立母体肥胖小鼠模型。我们发现肥胖时脂肪细胞释放含有大量NOX4的外泌体。这些外泌体进入循环，被胎盘滋养层吸收，导致ROS的大量产生和严重的DNA氧化损伤，最终在体内和体外诱导细胞周期停滞和细胞衰老。综上所述，脂肪组织可分泌含NOX4的外泌体，外泌体可被递送至滋养层，导致胎盘组织严重的DNA氧化损伤和过早衰老，从而导致不良妊娠结局。本研究有助于为改善肥胖妊娠胎盘早衰提供新的思路和实验证据。