Insights into the immunomodulatory regulation of matrix metalloproteinase at the maternal-fetal interface during early pregnancy and pregnancy-related diseases

Abstract

Trophoblast immune cell interactions are central events in the immune microenvironment at the maternal-fetal interface. Their abnormalities are potential causes of various pregnancy complications, including pre-eclampsia and recurrent spontaneous abortion. Matrix metalloproteinase (MMP) is highly homologous, zinc(II)-containing metalloproteinase involved in altered uterine hemodynamics, closely associated with uterine vascular remodeling. However, the interactions between MMP and the immune microenvironment remain unclear. Here we discuss the key roles and potential interplay of MMP with the immune microenvironment in the embryo implantation process and pregnancy-related diseases, which may contribute to understanding the establishment and maintenance of normal pregnancy and providing new therapeutic strategies. Recent studies have shown that several tissue inhibitors of metalloproteinases (TIMPs) effectively prevent invasive vascular disease by modulating the activity of MMP. We summarize the main findings of these studies and suggest the possibility of TIMPs as emerging biomarkers and potential therapeutic targets for a range of complications induced by abnormalities in the immune microenvironment at the maternal-fetal interface. MMP and TIMPs are promising targets for developing new immunotherapies to treat pregnancy-related diseases caused by immune imbalance.

The Uterine Melatonergic Systems of AANAT and Melatonin Membrane Receptor 2 (MT2) Are Essential for Endometrial Receptivity and Early Implantation in Mice

“…The elevated expression of MMP-2 and MMP-9 is well-documented in the phases of healthy pregnancy [ 54 ]. A change in MMP-2 expression or activity may relate to EGF-mediated trophoblast invasion [ 55 ]. High levels of MMP-9 promote extravillous trophoblast cell invasion by the promotion of the breakdown of the endometrial ECM and the loosening of intercellular connections [ 55 ] However, this ECM−receptor interaction is jeopardized in Aanat KO mice.…”

“…A change in MMP-2 expression or activity may relate to EGF-mediated trophoblast invasion [ 55 ]. High levels of MMP-9 promote extravillous trophoblast cell invasion by the promotion of the breakdown of the endometrial ECM and the loosening of intercellular connections [ 55 ] However, this ECM−receptor interaction is jeopardized in Aanat KO mice. The expression of MMP-2 and MMP-9 in the Aanat KO mice was downregulated compared to the WT mice.…”

The NFκB Signaling Pathway Is Involved in the Pathophysiological Process of Preeclampsia

“…MMPs are important extracellular matrix (ECM) remodeling proteinases that control uterine remodeling, a process that is essential for healthy pregnancies 26 . High MMP-9 levels promote uterine ECM degradation and relax intercellular connections, promoting extravillous trophoblast cells to invade and uterine spiral artery remodeling 27 28 .…”

Advances in Research on Aging in Female Infertility and Pathologic Pregnancy

“…Preeclampsia patients exhibit decreased expression of functional proteins such as matrix metalloproteinase (MMP) 2 and MMP9, as well as increased levels of phosphatidylserine (PS) and lower levels of phosphatidic acid and phosphatidylglycerol in exosomes when compared to the normal pregnancy group (63,64). The remodeling of spiral arteries, fetal growth, superficial placentation, reduced blood flow, and ultimately the development of Preeclampsia can all be impacted by decreased expression of any one of these proteins.…”