DAAM2 is elevated in the circulation and placenta in pregnancies complicated by fetal growth restriction and is regulated by hypoxia.
DAAM2 is elevated in the circulation and placenta in pregnancies complicated by fetal growth restriction and is regulated by hypoxia.
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DOI：
10.1038/s41598-021-84785-7
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发表时间：
2021-03-10
影响因子：
4.6
通讯作者：
Hannan NJ
中科院分区：
文献类型：
--
作者：
de Alwis N;Beard S;Binder NK;Pritchard N;Kaitu'u-Lino TJ;Walker SP;Stock O;Groom K;Petersen S;Henry A;Said JM;Seeho S;Kane SC;Hui L;Tong S;Hannan NJ
以前，我们发现孕妇循环DAAM 2 mRNA增加并发早产胎儿生长受限（FGR）。在这里，我们评估了循环DAAM 2 mRNA是否可以检测FGR，以及已知在Wnt信号通路中发挥作用的DAAM 2基因是否在人胎盘中表达并与功能障碍和FGR相关。我们进行了线性回归分析，以计算在合并早产FGR的妊娠母体循环中DAAM 2 mRNA表达的ROC曲线下面积（AUC）。通过qPCR评估整个妊娠期间的DAAM 2 mRNA表达。使用蛋白质印迹和qPCR评估早产FGR胎盘中DAAM 2蛋白和mRNA的表达。通过qPCR在缺氧和常氧条件下培养的足月细胞滋养层和胎盘外植体组织中评估DAAM 2表达。小干扰RNA用于沉默足月原代细胞滋养层中的DAAM 2。通过qPCR评估生长、凋亡和氧化应激基因的表达。在合并早产FGR的妊娠中，循环DAAM 2 mRNA升高[p < 0.0001，AUC = 0.83（0.78-0.89）]。胎盘DAAM 2 mRNA在整个妊娠期均可检测到，在足月时表达最高。DAAM 2蛋白在早产FGR胎盘中增加，但mRNA表达无变化。缺氧时细胞滋养层细胞和胎盘组织中DAAM 2 mRNA表达增加。在缺氧条件下沉默DAAM 2降低了促生存基因BCL 2和氧化应激标志物NOX 4的表达，同时增加了抗氧化酶HMOX-1的表达。与FGR和缺氧相关的DAAM 2增加暗示了胎盘功能障碍的潜在作用。减少DAAM 2可能具有细胞保护作用，但需要进一步研究以阐明其在健康和功能障碍胎盘中的作用。
Previously, we identified increased maternal circulating DAAM2 mRNA in pregnancies complicated by preterm fetal growth restriction (FGR). Here, we assessed whether circulating DAAM2 mRNA could detect FGR, and whether the DAAM2 gene, known to play roles in the Wnt signalling pathway is expressed in human placenta and associated with dysfunction and FGR. We performed linear regression analysis to calculate area under the ROC curve (AUC) for DAAM2 mRNA expression in the maternal circulation of pregnancies complicated by preterm FGR. DAAM2 mRNA expression was assessed across gestation by qPCR. DAAM2 protein and mRNA expression was assessed in preterm FGR placenta using western blot and qPCR. DAAM2 expression was assessed in term cytotrophoblasts and placental explant tissue cultured under hypoxic and normoxic conditions by qPCR. Small interfering RNAs were used to silence DAAM2 in term primary cytotrophoblasts. Expression of growth, apoptosis and oxidative stress genes were assessed by qPCR. Circulating DAAM2 mRNA was elevated in pregnancies complicated by preterm FGR [p < 0.0001, AUC = 0.83 (0.78–0.89)]. Placental DAAM2 mRNA was detectable across gestation, with highest expression at term. DAAM2 protein was increased in preterm FGR placentas but demonstrated no change in mRNA expression. DAAM2 mRNA expression was increased in cytotrophoblasts and placental explants under hypoxia. Silencing DAAM2 under hypoxia decreased expression of pro-survival gene, BCL2 and oxidative stress marker, NOX4, whilst increasing expression of antioxidant enzyme, HMOX-1. The increased DAAM2 associated with FGR and hypoxia implicates a potential role in placental dysfunction. Decreasing DAAM2 may have cytoprotective effects, but further research is required to elucidate its role in healthy and dysfunctional placentas.
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