维生素D缺乏经Hippo-YAP信号通路抑制胎盘发育诱发胎儿宫内生长受限

VITAMIN D DEFICIENCY INHIBITS PLACENTAL DEVELOPMENT AND INDUCES FETAL GROWTH RESTRICTION THROUGH HIPPO-YAP SIGNALING PATHWAY

目的探究维生素D(vitaminD,VD)缺乏经Hippo-YAP信号通路抑制胎盘的发育,进而导致胎儿宫内生长受限的发生机制。方法按照体质量将4w龄SD雌性大鼠随机分为VD缺乏组(vitamin D deficiency,VDD)与对照组(CTRL),VDD组采用VD缺乏饲料喂养,CTRL组采用标准饲料喂养,喂养8周后雌雄合笼。结果妊娠13d(GD13)与GD18时,VDD组孕鼠的血清25(OH)D浓度分别为(2.82±0.18)ng/ml和(14.67±7.92)ng/ml,对照组孕鼠的血清25(OH)D浓度分别为(36.58±10.58)ng/ml和(19.92±6.91)ng/ml,组间比较在GD13时有差异(P<0.0001)。GD13时,VDD组孕鼠的胚胎着床数(12.83±1.17)显著低于CTRL组的(15.83±1.47)(P<0.01);GD18时,VDD组孕鼠胚胎着床数(12.83±2.23),显著低于CTRL组的(15.67±1.03)(P<0.05),VDD组孕鼠的胎儿流产率也明显上升。GD18时,VDD组孕鼠的胎盘重量平均为(2.93±0.42)g,显著低于CTRL组的(6.38±0.48)g(P<0.0001);VDD组孕鼠的胎盘海绵体滋养层细胞面积为(11.63±0.03)%,显著小于CTRL组的(22.63±0.01)%(P<0.05);VDD组的活胎数,孕鼠孕期增重显著降低(P<0.01或P<0.0001),吸收胎数显著增加(P<0.05)。GD13时,与CTRL组相比,VDD组孕鼠胎盘组织中YAP1蛋白表达水平显著降低(P<0.01),P-YAP蛋白表达水平显著增高(P<0.001)。结论母体VD缺乏是导致妊娠后胚胎发育迟缓的重要原因,其机制可能涉及Hippo-YAP信号通路的激活,在孕前及孕期合理补充VD对胎儿健康具有重要意义。

Objective To explore the mechanism that vitamin D deficiency inhibits the development of placenta through Hippo-YAP signal pathway and then leads to fetal growth restriction.Methods Four-week-old SD female rats were randomly divided into vitamin D deficiency group(VDD)and control group(CTRL).The VDD group was fed a vitamin D deficiency diet and the CTRL group was fed a standard diet.Results On the 13th(GD13)and 18th(GD18)days of pregnancy,the concentration of serum 25(OH)D in the VDD group was(2.82±0.18)ng/ml and(14.67±7.92)ng/ml,while that in the control group was(36.58±10.58)ng/ml and(19.92±6.91)ng/ml,respectively.There was significant difference between the two groups at GD13(P<0.0001).At GD13,the number of embryo implantation in the VDD group(12.83±1.17)was significantly lower than that in the CTRL group(15.83±1.47)(P<0.01).At GD18,the number of embryo implantation in the VDD group(12.83±2.23)was significantly lower than that in the CTRL group(15.67±1.03)(P<0.05),and the fetal abortion rate in the VDD group was also significantly higher than that in the CTRL group.At GD18,the average placental weight of pregnant rats in the VDD group(2.93±0.42)g was significantly lower than that in the CTRL group(6.38±0.48)g(P<0.0001),and the area of placental cavernous trophoblast cells in the VDD group(11.63±0.03)%was significantly lower than that in the CTRL group(22.63±0.01)%(P<0.0001).In the VDD group,the number of live fetus and weight gain during pregnancy decreased significantly(P<0.01 or P<0.0001),while the number of absorbed fetus increased significantly(P<0.05).At GD13,compared with the CTRL group,the expression of YAP1 protein in the placenta of the VDD group decreased significantly(P<0.01),while the expression of P-YAP protein increased significantly(P<0.001).Conclusion Maternal vitamin D deficiency is an important cause of embryonic growth retardation after pregnancy,and its mechanism may involve the activation of Hippo-YAP signal pathway.Reasonable supplementation of vitamin D before and during pregnancy is of great significance to fetal health.