The role of trophoblastic adrenomedullin on placental development during early pregnancy and its association with early-onset preeclampsia

Abstract

Preeclampsia (PE) is a serious complication that affects 2-8% of all pregnancies and is defined as proteinuria gestational hypertension. PE is associated with defective spiral artery remodeling, but the underlying molecular mechanism of the defect remains elusive. Successful spiral artery remodeling includes the extravillous trophoblast from the placenta villi are recruited and then invade into the spiral arteries, and differentiation into endovascular trophoblast to replace the endothelial lining. Adrenomedullin (ADM) is a peptide hormone that belongs to the calcitonin/calcitonin gene-related peptide (CGRP)/amylin peptide family. Plasma ADM level is elevated after implantation and peaks in early pregnancy in humans, suggesting its early placentation involvement. Although ADM is found to have high trophoblast expression, its regulatory role in trophoblasts during the first trimester remains elusive. In this study, reduction of ADM expression in the cytotrophoblast layer and syncytiotrophoblast layer was not only found in term PE placental tissues but also placental CVS tissue from women in the first trimester. These women later develop PE at term. Using primary human trophoblasts isolated from the first-trimester placenta, we further revealed that ADM enhanced trophoblast migration, invasion, and integration into the endothelial network in vitro. Besides, ADM enhanced endothelial cell line HUVEC angiogenesis and reduced the permeability of the endothelial cell layer via the up-regulation of the cell junction markers in vitro. To explore the physiological functions of placenta-derived ADM in vivo, ADM expression in the placenta was suppressed using trophoblast-targeting nanoparticles in pregnant mice. Consistently, trophoblast-specific knockdown of ADM resulted in a defective labyrinthine structure in the placenta, increased abortion rate in pregnant mice, and reduced fetus weight. Histopathological analysis revealed alterations in placenta morphology, including reduced branching structures and defects in the development of syncytiotrophoblast II, spongiotrophoblast/glycogen trophoblast and fetus blood vessel formation. These data indicated that ADM contributed to early placenta development through modulating trophoblast and endothelial cell functions. The down-regulation of ADM contributed to the pathophysiology of PE by altering trophoblast differentiation and functions. Overall, this studies not only provide insights into the role of ADM in placental development and pathophysiology to PE but also further suggest the intriguing possibility of using ADM as a potential early detection biomarker of PE and highlight the importance of modest alterations of ADM gene expression in trophoblast as a therapeutic target of PE.