Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina 27599, USA.
J Clin Invest. 2013 Jun;123(6):2408-20. doi: 10.1172/JCI67039. Epub 2013 May 1.
The remodeling of maternal uterine spiral arteries (SAs) is an essential process for ensuring low-resistance, high-capacitance blood flow to the growing fetus. Failure of SAs to remodel is causally associated with preeclampsia, a common and life-threatening complication of pregnancy that is harmful to both mother and fetus. Here, using both loss-of-function and gain-of-function genetic mouse models, we show that expression of the pregnancy-related peptide adrenomedullin (AM) by fetal trophoblast cells is necessary and sufficient to promote appropriate recruitment and activation of maternal uterine NK (uNK) cells to the placenta and ultimately facilitate remodeling of maternal SAs. Placentas that lacked either AM or its receptor exhibited reduced fetal vessel branching in the labyrinth, failed SA remodeling and reendothelialization, and markedly reduced numbers of maternal uNK cells. In contrast, overexpression of AM caused a reversal of these phenotypes with a concomitant increase in uNK cell content in vivo. Moreover, AM dose-dependently stimulated the secretion of numerous chemokines, cytokines, and MMPs from uNK cells, which in turn induced VSMC apoptosis. These data identify an essential function for fetal-derived factors in the maternal vascular adaptation to pregnancy and underscore the importance of exploring AM as a biomarker and therapeutic agent for preeclampsia.
母体子宫螺旋动脉（SAs）的重塑是确保向生长中的胎儿提供低阻力、高容量血流的重要过程。如果 SAs 重塑失败，就会导致子痫前期，这是一种常见且危及生命的妊娠并发症，对母亲和胎儿都有害。在这里，我们使用功能丧失和功能获得的遗传小鼠模型，表明胎儿滋养层细胞表达与妊娠相关的肽类肾上腺髓质素（AM）对于促进母体子宫 NK（uNK）细胞向胎盘的适当募集和激活是必要和充分的，最终促进母体 SAs 的重塑。缺乏 AM 或其受体的胎盘表现出胎儿血管在绒毛中分支减少、SA 重塑和再内皮化失败，以及母体 uNK 细胞数量明显减少。相比之下，AM 的过表达导致这些表型逆转，同时体内 uNK 细胞含量增加。此外，AM 呈剂量依赖性刺激 uNK 细胞分泌大量趋化因子、细胞因子和 MMPs，进而诱导血管平滑肌细胞凋亡。这些数据确定了胎儿来源的因子在母体血管适应妊娠中的重要作用，并强调了探索 AM 作为子痫前期生物标志物和治疗剂的重要性。
