抑制Hippo-YAP信号通路的激活对维生素D缺乏所致大鼠不良妊娠结局的改善作用

INHIBITION OF HIPPO-YAP SIGNALING PATHWAY IS EFFECTIVE IN IMPROVING ADVERSE PREGNANCY OUTCOMES CAUSED BY VITAMIN D DEFICIENCY IN RATS

目的探讨抑制Hippo-YAP信号通路的激活是否能改善维生素D缺乏(vitamin D deficiency,VDD)所导致的胎盘及胚胎发育不良。方法按照体质量将4w龄SD雌性大鼠随机分为对照组(Ctrl)、VD缺乏组(VDD)、VD缺乏阴性对照组(VDD+vehicle)与VD缺乏抑制剂组(VDD+XMU-MP-1),Ctrl组采用标准饲料喂养,VDD组采用VD缺乏饲料喂养,喂养8 w后雌雄合笼。VDD+vehicle组与VDD+XMU-MP-1组在妊娠0-10 d(GD 0-10)进行腹腔注射。结果VD缺乏8 w后,与Ctrl组相比,VDD组血清25(OH)D水平均降低,且Ctrl组与VDD组、VDD+vehicle组间差异均有统计学差异(P<0.05);GD18时,与Ctrl组相比,VDD组血清25(OH)D水平略有降低。GD18时,与Ctrl组相比,VDD组、VDD+vehicle组(P<0.01)及VDD+XMU-MP-1组(P<0.01)胎盘25(OH)D水平均降低;与Ctrl组相比,其他三组胎盘1,25(OH)2D水平均有所降低,且Ctrl组与VDD+vehicle组、VDD+XMU-MP-1组均有统计学差异(P<0.01)。与Ctrl组相比,VDD组胎盘(P<0.01)、胚胎(P<0.05)重量明显下降,与VDD+vehicle组相比,VDD+XMU-MP-1组胎盘重量有所增加,组间有统计学差异(P<0.05),而胚胎重量略有增加;与Ctrl组相比,VDD组胎盘直径、胚胎冠臀长明显降低,且均有统计学差异(P<0.01),与VDD+vehicle组相比,VDD+XMU-MP-1组胎盘直径(P<0.05)、胚胎冠臀长(P<0.01)有所增加。结论维生素D缺乏对胚胎发育的损害作用涉及胎盘组织Hippo-YAP通路的激活,Hippo-YAP信号通路可能是预防维生素D缺乏所致不良妊娠结局的潜在靶点。

Objective To investigate whether inhibition of Hippo-Yap signaling pathway can improve placental and embryonic dysplasia caused by vitamin D deficiency(VDD).Methods Based on body weight,female SD rats aged 4 weeks were randomly divided into control group(Ctrl),VDD group,VDD negative control group(VDD+vehicle),and VDD inhibitor group(VDD+XMU-MP-1).The Ctrl group was fed a standard diet,and the VDD group was fed a VD deficient diet.After 8 weeks of feeding,male and female rats were mated.The VDD+vehicle group and the VDD+XMU-MP-1 group received intraperitoned injection of vehicle or XMU-MP-1 at 0-10d of gestation(GD0-10).Results After 8w of VD deficiency,serum 25(OH)D levels in the VDD group were decreased compared with the Ctrl group,and there were statistical differences between the three groups(P<0.05).On GD18,serum 25(OH)D levels were slightly lower in the VDD group than in the Ctrl group.On GD18,compared with the Ctrl group,the levels of placenta 25(OH)D in the VDD group,VDD+vehicle group(P<0.01)and VDD+XMU-MP-1 group(P<0.01)were decreased.Compared with the Ctrl group,the placental 1,25(OH)2D levels in the other three groups were decreased,and there was a statistical difference between the Ctrl group and the VDD+vehicle group,VDD+XMU-MP-1 group(P<0.01).Compared with the Ctrl group,the weights of placenta(P<0.01)and embryo(P<0.05)in the VDD group decreased significantly.Compared with the VDD+vehicle group,the weight of placenta in the VDD+XMU-MP-1 group increased,with statistical difference between two groups(P<0.05),while the weight of embryo increased slightly.Compared with the Ctrl group,the placental diameter and fetal crown hip length in the VDD group were significantly decreased,with statistical differences(P<0.01).Compared with the VDD+vehicle group,the placental diameter(P<0.05)and fetal crown hip length in the VDD+XMU-MP-1 group were increased(P<0.01).Conclusion The damaging effect of VDD on fetal development involves the activation of Hippo-Yap pathway in placental tissue,which may be a potential target for preventing adverse pregnancy outcomes caused by VDD.