Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia

Abstract

Normal pregnancy is associated with marked hemodynamic and uterine changes that allow adequate uteroplacental blood flow and uterine expansion for the growing fetus. These pregnancy-associated changes involve significant uteroplacental and vascular remodeling. Matrix metalloproteinases (MMPs) are important regulators of vascular and uterine remodeling. Increases in MMP-2 and MMP-9 have been implicated in vasodilation, placentation and uterine expansion during normal pregnancy. The increases in MMPs could be induced by the increased production of estrogen and progesterone during pregnancy. MMP expression/activity may be altered during complications of pregnancy. Decreased vascular MMP-2 and MMP-9 may lead to decreased vasodilation, increased vasoconstriction, hypertensive pregnancy and preeclampsia. Abnormal expression of uteroplacental integrins, cytokines and MMPs may lead to decreased maternal tolerance, apoptosis of invasive trophoblast cells, inadequate remodeling of spiral arteries, and reduced uterine perfusion pressure (RUPP). RUPP may cause imbalance between the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the pro-angiogenic vascular endothelial growth factor and placental growth factor, or stimulate the release of inflammatory cytokines, hypoxia-inducible factor, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors could target MMPs in the extracellular matrix as well as endothelial and vascular smooth muscle cells, causing generalized vascular dysfunction, increased vasoconstriction and hypertension in pregnancy. MMP activity can also be altered by endogenous tissue inhibitors of metalloproteinases (TIMPs) and changes in the MMP/TIMP ratio. In addition to their vascular effects, decreases in expression/activity of MMP-2 and MMP-9 in the uterus could impede uterine growth and expansion and lead to premature labor. Understanding the role of MMPs in uteroplacental and vascular remodeling and function could help design new approaches for prediction and management of preeclampsia and premature labor.

Whole-Genome Uterine Artery Transcriptome Profiling and Alternative Splicing Analysis in Rat Pregnancy

“…It is widely accepted that the circumferential enlargement, along with axial elongation of the pregnant UA is mediated by substantial changes in several local genes [3]. Studies from our lab and others have shown explicit evidence for vascular specific transcriptional activation of unique genes (e.g., MMPs and TIMPs and estrogen receptor-ESR2) in gestational uterine vascular remodeling [45][46][47][48]. In the current study, the overall global changes in the uterine vasculature transcriptome activate a majority of pathways related to the local and peripheral immune response, which may help to tolerate the semi-allogeneic fetus [49].…”

“…Similarly, chymotrypsin-like serine endopeptidases are major serine proteases in human arteries responsible for angiotensin-converting enzyme (ACE)-independent production of angiotensin II, which play a significant role in vascular remodeling and contraction [62]. MMPs are another group of endopeptidases that degrade various proteins in the extracellular matrix (ECM), including collagen and elastin [45], which determines vascular remodeling, angiogenesis, and the systemic changes in blood pressure in healthy pregnancy [45,63]. On the other hand, the attenuated UA methyltransferase activity, which is involved in DNA/RNA and histone methylation, is shown to contribute to the decrease in the KCNMB1 promoter CpG methylation in pregnant ovine UA [64].…”

integRATE: a desirability-based data integration framework for the prioritization of candidate genes across heterogeneous omics and its application to preterm birth

“…Interestingly, MMP9 has been linked not only to sPTB, but also to PPROM and PE across a number of fetal and maternal tissues and at a variety of time points during pregnancy [63][64][65][66][67].…”

Therapeutics targeting the fibrinolytic system

“…Moreover, plasmin is the activator of multiple functional proteins. For instance, plasmin activates the generation of over 7 matrix metalloproteinases (MMPs) 6 , which directly participate in the processes of tissue remodeling, cancer progression, pregnancy, etc [7][8][9] . Beyond its fibrinolytic property, plasmin also has anti-coagulative effects by degrading factors V and VIII, thus blocking coagulation cascades 10 .…”