Role of ADAM and ADAMTS disintegrin and metalloproteinases in normal pregnancy and preeclampsia

Abstract

Normal pregnancy (NP) involves intricate processes starting with egg fertilization, proceeding to embryo implantation, placentation and gestation, and culminating in parturition. These pregnancy-related processes require marked uteroplacental and vascular remodeling by proteolytic enzymes and metalloproteinases. A disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motifs (ADAMTS) are members of the zinc-dependent family of proteinases with highly conserved protein structure and sequence homology, which include a pro-domain, and a metalloproteinase, disintegrin and cysteine-rich domain. In NP, ADAMs and ADAMTS regulate sperm-egg fusion, embryo implantation, trophoblast invasion, placental angiogenesis and spiral arteries remodeling through their ectodomain proteolysis of cell surface cytokines, cadherins and growth factors as well as their adhesion with integrins and cell-cell junction proteins. Preeclampsia (PE) is a serious complication of pregnancy characterized by new-onset hypertension (HTN) in pregnancy (HTN-Preg) at or after 20 weeks of gestation, with or without proteinuria. Insufficient trophoblast invasion of the uterine wall, inadequate expansive remodeling of the spiral arteries, reduced uteroplacental perfusion pressure, and placental ischemia/hypoxia are major initiating events in the pathogenesis of PE. Placental ischemia/hypoxia increase the release of reactive oxygen species (ROS), which lead to aberrant expression/activity of certain ADAMs and ADAMTS. In PE, abnormal expression/activity of specific ADAMs and ADAMTS that function as proteolytic sheddases could alter proangiogenic and growth factors, and promote the release of antiangiogenic factors and inflammatory cytokines into the placenta and maternal circulation leading to generalized inflammation, endothelial cell injury and HTN-Preg, renal injury and proteinuria, and further decreases in uteroplacental blood flow, exaggeration of placental ischemia, and consequently fetal growth restriction. Identifying the role of ADAMs and ADAMTS in NP and PE has led to a better understanding of the underlying molecular and vascular pathways, and advanced the potential for novel biomarkers for prediction and early detection, and new approaches for the management of PE.

Keywords: Endothelium; Extracellular matrix; Hypertension; Matrix metalloproteinases; Placenta; Preeclampsia; Remodeling; Uterus; Vascular smooth muscle.