脂联素通过上调PPARα/HOXA10通路改善多囊卵巢综合征大鼠的子宫内膜容受性

Adiponectin improves endometrial receptivity in rats with polycystic ovary syndrome by upregulating the PPARα/HOXA10 pathway

目的探讨脂联素(APN)是否可通过PPARα/HOXA10通路改善多囊卵巢综合征(PCOS)大鼠子宫内膜容受性。方法6周龄雌性SD大鼠随机分为对照组(CON,n=10)和PCOS模型组(n=40)。用来曲唑[1 mg/(kg·d)]建立PCOS大鼠模型后,再随机分为4组(n=10):模型对照组(PCOS),APN干预组(PCOS+APN)、APN联合PPARα抑制剂(GW6471)干预组(PCOS+APN+GW)及APN联合玉米油溶剂(vehicle,VEH)对照组(PCOS+APN+VEH);后3组大鼠均给与APN[10μg/(kg·d)]干预20 d。在给APN的第11天,PCOS+APN+GW组同时给与GW6471[1 mg/(kg·d)]作为阴性对照,PCOS+APN+VEH组同时给与vehicle(0.1 mL/d)作为阳性对照。检测大鼠动情周期、卵巢和子宫指数及其形态学变化、血清激素及生化指标的改变。免疫组化和Western blot检测PPARα和HOXA10蛋白的表达,电镜观察子宫内膜胞饮突的发育情况,合笼实验观察大鼠的妊娠情况。结果与CON组比较,PCOS组大鼠动情周期紊乱,多处于动情间期;平均体质量和卵巢指数增加、子宫指数下降(P<0.05),血清激素与脂质代谢异常,卵巢多囊样改变;给与APN干预后各组各项指标均得到恢复。子宫内膜组织中PPARα和HOXA10的表达:在PCOS组较CON组显著下调(P<0.05)、在PCOS+APN组中较PCOS组显著上调(P<0.05)、在PCOS+APN+GW组中较PCOS+APN组及PCOS+APN+VEH组则显著下调(P<0.05)。与CON组比较,PCOS组大鼠子宫内膜胞饮突发育欠佳;PCOS+APN组胞饮突发育较PCOS组良好;与PCOS+APN组比较,PCOS+APN+GW组胞饮突发育欠佳;与PCOS+APN+GW组比较,PCOS+APN+VEH组胞饮突发育良好。与PCOS组比较,各组大鼠妊娠率一致;但PCOS+APN+GW组大鼠胚胎数量相对于PCOS+APN组显著减少且发育迟缓。结论APN可通过上调PPARα/HOXA10通路改善PCOS大鼠子宫内膜容受性,该结果有望为改善PCOS病人妊娠结局的治疗提供实验依据。

Objective To explore the role of the PPARα/HOXA10 signaling pathway in mediating the effect of adiponectin(APN)for improving endometrial receptivity in a rat model of polycystic ovary syndrome(PCOS).Methods Forty female SD rat models with letrozole-induced PCOS were randomized,with 10 normal rats as the control,into 4 equal groups for treatment with APN alone,APN combined with GW6471(a specific PPARαinhibitor)or the vehicle for 20 days,or no further treatment(PCOS model group).GW6471 treatment(daily dose of 1 mg/kg)and vehicle treatment were initiated on the 11th day following the start of APN treatment,all administered via intraperitoneal injection.The rats were observed for changes in estrous cycle,body weight,ovarian index and morphology,uterine index and morphology,serum hormone levels and lipid metabolism parameters.Endometrial expressions of PPARαand HOXA10 were detected with immunohistochemistry and Western blotting.The development of endometrial pinopodes was observed under electron microscope,and pregnancies of the rats were recorded.Results The rat models of PCOS exhibited obvious estrous cycle disorders with significantly prolonged estrous interval,increased body weight and ovarian index,decreased uterine index,disordered serum hormones and lipid metabolism(P<0.05),and polycystic ovarian changes,and these changes were significantly improved by APN treatment.Endometrial expressions of PPARαand HOXA10 were significantly lowered in PCOS rats and effectively up-regulated after APN treatment,but GW6471 treatment obviously blocked the effect of APN(P<0.05).APN showed strong protective effect against PCOS-induced impairment of endometrial pinopode development,and this effect was obviously attenuated by GW6471.APN also significantly increased the pregnancy rate and embryo number in PCOS rats,while GW6471 obviously reduced the embryo number and caused developmental retardation of the embryos.Conclusion APN can improve endometrial receptivity in PCOS rats by upregulating the PARα/HOXA10 pathway.