Excess LIGHT contributes to placental impairment, increased secretion of vasoactive factors, hypertension, and proteinuria in preeclampsia.
Excess LIGHT contributes to placental impairment, increased secretion of vasoactive factors, hypertension, and proteinuria in preeclampsia.
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DOI：
10.1161/hypertensionaha.113.02458
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发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Xia Y
中科院分区：
文献类型：
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作者：
Wang W;Parchim NF;Iriyama T;Luo R;Zhao C;Liu C;Irani RA;Zhang W;Ning C;Zhang Y;Blackwell SC;Chen L;Tao L;Hicks MJ;Kellems RE;Xia Y
先兆子痫（PE），一种常见的妊娠高血压疾病，被认为是继发于子宫胎盘缺血。越来越多的证据表明，包括炎症细胞因子和生长因子在内的缺氧非依赖性介质与PE有关，但尚不清楚这些信号是否直接导致胎盘损伤和体内疾病的发展。我们报道，与血压正常的孕妇相比，LIGHT，一种新的TNF超家族成员，在子痫前期妇女的循环和胎盘中显著升高。妊娠小鼠注射LIGHT可诱导胎盘凋亡、胎儿小以及pe -高血压和蛋白尿的关键特征。从机制上说，我们利用光受体特异性的中和抗体，发现光受体、疱疹病毒进入介质（HVEM）和淋巴素β受体（LTβR）是光诱导的妊娠小鼠胎盘损伤、小胎儿和PE特征所必需的。因此，我们进一步揭示了LIGHT通过这两个受体诱导可溶性类蛋白酪氨酸激酶-1 （sFlt-1）和内皮素-1 （ET-1）这两个公认的PE致病因子的分泌，从而在妊娠小鼠高血压和蛋白尿中发挥重要作用。最后，我们将动物研究结果扩展到人类研究，证明了光受体的激活导致人胎盘绒毛外植体细胞凋亡增加和sFlt-1分泌升高。总的来说，我们的人类和小鼠研究表明，LIGHT信号是一种以前未被认识的途径，负责胎盘凋亡、血管活性因子分泌升高和PE的后续母体特征，并为疾病管理提供了新的治疗机会。
Preeclampsia (PE), a prevalent hypertensive disorder of pregnancy, is believed to be secondary to uteroplacental ischemia. Accumulating evidence indicates that hypoxia-independent mediators, including inflammatory cytokines and growth factors, are associated with PE, but it is unclear whether these signals directly contribute to placental damage and disease development in vivo. We report that LIGHT, a novel TNF superfamily member, is significantly elevated in the circulation and placentas of preeclamptic women compared to normotensive pregnant individuals. Injection of LIGHT into pregnant mice induced placental apoptosis, small fetuses and key features of PE-hypertension and proteinuria. Mechanistically, using neutralizing antibodies specific for LIGHT receptors, we found that the LIGHT receptors, herpes virus entry mediator (HVEM) and lymphotoxin β receptor (LTβR), are required for LIGHT-induced placental impairment, small fetuses and PE features in pregnant mice. Accordingly, we further revealed that LIGHT functions through these two receptors to induce secretion of soluble fms-like tyrosine kinase-1 (sFlt-1) and endothelin-1 (ET-1), two well-accepted pathogenic factors in PE, and thereby plays an important role in hypertension and proteinuria in pregnant mice. Lastly, we extended our animal findings to human studies and demonstrated that activation of LIGHT receptors resulted in increased apoptosis and elevation of sFlt-1 secretion in human placental villous explants. Overall, our human and mouse studies show that LIGHT signaling is a previously unrecognized pathway responsible for placental apoptosis, elevated secretion of vasoactive factors and subsequent maternal features of PE and reveal new therapeutic opportunities for the management of disease.