背景:胎儿生长受限(FGR)是一种妊娠并发症,其中新生儿无法实现其生长潜力,增加围产期发病率和死亡率的风险。慢性母体妊娠缺氧,以及胎盘功能不全与FGR发病率增加有关;然而,FGR的分子机制尚不清楚.
方法:使妊娠小鼠经受急性或慢性缺氧(12.5%O2),导致胎儿体重降低。通过血氧水平依赖性(BOLD)对比磁共振成像(MRI)评估胎盘氧转运。通过免疫组织化学和原位杂交分析胎盘。从FGR和匹配的对照中选择人胎盘,并通过免疫组织化学(IHC)进行分析。通过质谱法分析母体和脐带血清。
结果:我们显示小鼠急性和慢性妊娠缺氧可重现FGR表型并影响胎盘结构和形态。妊娠缺氧迷宫面积减少,在扩大胎盘螺旋动脉(SpA)直径的同时,增加了迷宫中红细胞(RBC)的发生率。与对照组相比,低氧胎盘表现出更高的血红蛋白-氧亲和力。与对照组相比,小鼠妊娠缺氧组的合胞体滋养层和螺旋动脉滋养层细胞(SpATGC)中胎盘双磷酸甘油酸变位酶(BPGM)的丰度上调。与对照组相比,急性缺氧组的Hif1a水平更高。相比之下,与健康无并发症妊娠的胎盘相比,人FGR胎盘在合胞体滋养层中的BPGM水平降低。2,3BPG的水平,BPGM的产品,与对照组相比,人FGR胎盘的脐带血清较低。BPGM的极性表达,在人类和小鼠胎盘合胞体滋养层中都有发现,面向母体循环具有较高的表达。此外,在鼠SpATGCs中,BPGM的表达仅集中在顶端细胞侧,紧邻母体循环。
结论:本研究提示胎盘BPGM可能参与母胎氧转移,以及FGR的病理生理学。
资助:这项工作得到了WeizmannKrenter基金会和Weizmann-Ichilov(特拉维夫Sourasky医学中心)生物医学研究合作资助的支持,和密涅瓦基金会(MN),由ISFKillCorona授予3777/19(给MN,MK)。
UNASSIGNED: Fetal growth restriction (FGR) is a pregnancy complication in which a newborn fails to achieve its growth potential, increasing the risk of perinatal morbidity and mortality. Chronic maternal gestational hypoxia, as well as placental insufficiency are associated with increased FGR incidence; however, the molecular mechanisms underlying FGR remain unknown.
UNASSIGNED: Pregnant mice were subjected to acute or chronic hypoxia (12.5% O2) resulting in reduced fetal weight. Placenta oxygen transport was assessed by blood oxygenation level dependent (BOLD) contrast magnetic resonance imaging (MRI). The placentae were analyzed via immunohistochemistry and in situ hybridization. Human placentae were selected from FGR and matched controls and analyzed by immunohistochemistry (IHC). Maternal and cord sera were analyzed by mass spectrometry.
UNASSIGNED: We show that murine acute and chronic gestational hypoxia recapitulates FGR phenotype and affects placental structure and morphology. Gestational hypoxia decreased labyrinth area, increased the incidence of red blood cells (RBCs) in the labyrinth while expanding the placental spiral arteries (SpA) diameter. Hypoxic placentae exhibited higher hemoglobin-oxygen affinity compared to the control. Placental abundance of Bisphosphoglycerate mutase (BPGM) was upregulated in the syncytiotrophoblast and spiral artery trophoblast cells (SpA TGCs) in the murine gestational hypoxia groups compared to the control. Hif1α levels were higher in the acute hypoxia group compared to the control. In contrast, human FGR placentae exhibited reduced BPGM levels in the syncytiotrophoblast layer compared to placentae from healthy uncomplicated pregnancies. Levels of 2,3 BPG, the product of BPGM, were lower in cord serum of human FGR placentae compared to control. Polar expression of BPGM was found in both human and mouse placentae syncytiotrophoblast, with higher expression facing the maternal circulation. Moreover, in the murine SpA TGCs expression of BPGM was concentrated exclusively in the apical cell side, in direct proximity to the maternal circulation.
UNASSIGNED: This
study suggests a possible involvement of placental BPGM in maternal-fetal oxygen transfer, and in the pathophysiology of FGR.
UNASSIGNED: This work was supported by the Weizmann Krenter Foundation and the Weizmann - Ichilov (Tel Aviv Sourasky Medical Center) Collaborative Grant in Biomedical Research, by the Minerva Foundation, by the ISF KillCorona grant 3777/19.