Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade various proteins in the extracellular matrix (ECM). Typically, MMPs have a propeptide sequence, a catalytic metalloproteinase domain with catalytic zinc, a hinge region or linker peptide, and a hemopexin domain. MMPs are commonly classified on the basis of their substrates and the organization of their structural domains into collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and other MMPs. MMPs are secreted by many cells including fibroblasts, vascular smooth muscle (VSM), and leukocytes. MMPs are regulated at the level of mRNA expression and by activation through removal of the propeptide domain from their latent zymogen form. MMPs are often secreted in an inactive proMMP form, which is cleaved to the active form by various proteinases including other MMPs. MMPs degrade various protein substrates in ECM including collagen and elastin. MMPs could also influence endothelial cell function as well as VSM cell migration, proliferation, Ca2+ signaling, and contraction. MMPs play a role in vascular tissue remodeling during various biological processes such as angiogenesis, embryogenesis, morphogenesis, and wound repair. Alterations in specific MMPs could influence arterial remodeling and lead to various pathological disorders such as hypertension, preeclampsia, atherosclerosis, aneurysm formation, as well as excessive venous dilation and lower extremity venous disease. MMPs are often regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP ratio often determines the extent of ECM protein degradation and tissue remodeling. MMPs may serve as biomarkers and potential therapeutic targets for certain vascular disorders.

Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease

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 antiangiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the proangiogenic 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

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Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia.

Preeclampsia is a pregnancy-related disorder characterized by hypertension and could lead to maternal and fetal morbidity and mortality. Although the causative factors and pathophysiological mechanisms are unclear, endothelial dysfunction is a major hallmark of preeclampsia. Clinical tests and experimental research have suggested that generalized endotheliosis in the systemic, renal, cerebral, and hepatic circulation could decrease endothelium-derived vasodilators such as nitric oxide, prostacyclin, and hyperpolarization factor and increase vasoconstrictors such as endothelin-1 and thromboxane A2, leading to increased vasoconstriction, hypertension, and other manifestation of preeclampsia. In search for the upstream mechanisms that could cause endothelial dysfunction, certain genetic, demographic, and environmental risk factors have been suggested to cause abnormal expression of uteroplacental integrins, cytokines, and matrix metalloproteinases, leading to decreased maternal tolerance, apoptosis of invasive trophoblast cells, inadequate spiral arteries remodeling, reduced uterine perfusion pressure (RUPP), and placental ischemia/hypoxia. RUPP may cause imbalance between the antiangiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the proangiogenic factors vascular endothelial growth factor and placental growth factor, or stimulate the release of other circulating bioactive factors such as inflammatory cytokines, hypoxia-inducible factor-1, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors could then target endothelial cells and cause generalized endothelial dysfunction. Therapeutic options are currently limited, but understanding the factors involved in endothelial dysfunction could help design new approaches for prediction and management of preeclampsia.

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Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

// Xiao-Xiang Jie 1, 2, 3 , Xiao-Yan Zhang 1, 2, 3 and Cong-Jian Xu 1, 2, 3, 4 1 Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, People’s Republic of China 2 Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai 200032, People’s Republic of China 3 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, People’s Republic of China 4 Institute of Biomedical Sciences, Fudan University, Shanghai 200032, People’s Republic of China Correspondence to: Xiao-Yan Zhang, email: xyzhang80@gmailcom Cong-Jian Xu, email: xucongjian@gmailcom Keywords: epithelial-to-mesenchymal transition, circulating tumor cells, metastasis, EMT markers Received: March 29, 2017      Accepted: May 10, 2017      Published: May 26, 2017 ABSTRACT Epithelial-to-mesenchymal transition (EMT) endows epithelial cells with enhanced motility and invasiveness, allowing them to participate in many physiological and pathological processes Epithelial-to-mesenchymal transition contributes to the generation of circulating tumor cells (CTCs) in epithelial cancers because it increases tumor cell invasiveness, promotes tumor cell intravasation and ensures tumor cell survival in the peripheral system Although the contribution of epithelial-to-mesenchymal transition to tumor cell invasiveness has been confirmed, the role epithelial-to-mesenchymal transition plays in metastasis remains debated As a favorable material for a “liquid biopsy”, circulating tumor cells have been shown to have promising values in the clinical management of tumors Furthermore, an increasing number of studies have begun to explore the value of CTC-related biomarkers, and some studies have found that the expression of EMT and stemness markers in circulating tumor cells, in addition to CTC detection, can provide more information on tumor diagnosis, treatment, prognosis and research

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Epithelial-to-mesenchymal transition, circulating tumor cells and cancer metastasis: Mechanisms and clinical applications

Trophoblast migration and invasion through the decidua and maternal uterine spiral arteries are crucial events in placentation. During this process, invasive trophoblast replace vascular endothelial cells as the uterine arteries are remodeled to form more permissive vessels that facilitate adequate blood flow to the growing fetus. Placentation failures resulting from either extensive or shallow trophoblastic invasion can cause pregnancy complications such as preeclampsia, intrauterine growth restriction, placenta creta, gestational trophoblastic disease and even maternal or fetal death. Consequently, the use of experimental animal models such as rats and mice has led to great progress in recent years with regards to the identification of mechanisms and factors that control trophoblast migration kinetics. This review aims to perform a comparative analysis of placentation and the mechanisms and factors that coordinate intrauterine trophoblast migration in humans, rats and mice under physiological and pathological conditions.

https://www.tandfonline.com/doi/pdf/10.1080/19336918.2015.1120397

Intrauterine trophoblast migration: A comparative view of humans and rodents.

MicroRNA-204 suppresses trophoblast-like cell invasion by targeting matrix metalloproteinase-9.

Objective:To test the effects of human umbilical cord mesenchymal stem cell (HU-MSC) transplantation on reversing preeclampsia (PE) symptoms in a lipopolysaccharide (LPS)-induced rat PE model.Methods:Human umbilical cord MSCs were detected, isolated, and cultured. Human umbilical cord MSC transplantation was conducted. Expressions of inflammatory cytokines in serum and placental tissue were measured by enzyme-linked immunosorbent assay. Changes in inflammatory cytokines, peroxisome proliferator-activated receptor γ (PPARγ), laminin receptor 1 (LR1), matrix metalloproteinase (MMP) 2, and MMP-9 messenger RNA (mRNA) levels in placental tissue were recorded by quantitative real-time polymerase chain reaction. Immunohistochemistry and Western blotting were performed for PPARγ detection.Results:The LPS group exhibited increased blood pressure and proteinuria and decreased fetal weight compared to the normal pregnancy (NP) group (all P < .05). The LPS + MSC group presented lowered blood pressure and higher fetal...

Effect of Human Umbilical Cord Mesenchymal Stem Cell Transplantation in a Rat Model of Preeclampsia.

Immunomodulation by mesenchymal stem cells (MSCs) is potentially important for maintaining peripheral tolerance. Preeclampsia may be due to maternal immune rejection of the genetically foreign fetus. This study aimed to investigate the biological function of human umbilical cord-derived mesenchymal stem cells (HU-MSCs) for the treatment of angiotensin receptor agonistic autoantibody (AT1-AA)-induced hypertension during pregnancy. HU-MSCs were isolated, cultured, and labeled in vitro. AT1-AA and HU-MSCs were administered to pregnant rats. Green fluorescent protein (GFP)-positive HU-MSCs infused in vivo were identified by immunofluorescence. Systolic blood pressure (SBP) was evaluated. The effects of HU-MSCs on fetal weight, kidney burden, and spiral artery remodeling, as well as on the expression of tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), and heme oxygenase 1 (HO-1), were investigated. The SBP levels in the HU-MSC-treated pregnant hypertension rats decreased by gestational day 19. The reduction in fetal weight was largely ameliorated after HU-MSC treatment. Lesion burden in the kidney was attenuated and spiral artery remodeling was improved in HU-MSC-treated pregnant hypertension rats. However, green fluorescent protein (GFP)-labeled cells were sparingly observed in the kidney and placenta. Intravenous infusion of HU-MSCs into AT1-AA-induced rats significantly downregulated serum TNF-α levels and upregulated IL-10 levels, concomitant with increased placenta and mesometrial triangle (MT) HO-1 expression. Taken together, intravenous infusion of HU-MSCs ameliorates AT1-AA-induced pregnancy hypertension, intrauterine growth retardation, kidney impairment, and spiral artery remodeling impairment. Moreover, the potential benefits of HU-MSCs may be attributable to both an interference with the pathogenic immune response and a paracrine cytoprotective action.

Therapeutic benefit of mesenchymal stem cells in pregnant rats with angiotensin receptor agonistic autoantibody-induced hypertension: Implications for immunomodulation and cytoprotection.

Shallow trophoblast invasion is a common pathological feature of preeclampsia. The 67 kDa laminin receptor 1 (LR1) is a laminin-binding protein that has been reported to be down-regulated in preeclamptic placentas. The aim of the present study was to determine the functional role of LR1 in the migration and invasion of the trophoblast cell line, JEG3 cells. RNA interference mediated by plasmid expressing LR1 short hairpin RNA (shRNA) was utilized to knockdown LR1 expression in JEG3 cells. We found that the mRNA and protein expression levels of LR1 were significantly reduced in LR1-specific shRNA transfected cells compared with the untransfected and control shRNA transfected cells. The wound healing and Transwell invasion assays demonstrated that LR1 knockdown remarkably suppressed the migration and invasion potential of JEG3 cells. The gelatin zymography assay showed that LR1 knockdown greatly reduced matrix metalloproteinase (MMP)-2 and MMP-9 activities in the culture supernatants. Western blot analysis showed that LR1 shRNA significantly decreased expression levels of MMP-2, MMP-9 and phospho-extracellular signal-regulated kinase, but increased expression levels of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in comparison to the control vector-transfected cells. In conclusion, our data support an important role for LR1 in regulating trophoblast invasion and migration, and suggest a possible pathological mechanism of preeclampsia.

RNA interference-mediated silencing of laminin receptor 1 (LR1) suppresses migration and invasion and down-regulates matrix metalloproteinase (MMP)-2 and MMP-9 in trophoblast cells: implication in the pathogenesis of preeclampsia

RNA interference-mediated knockdown of Notch-1 inhibits migration and invasion, down-regulates matrix metalloproteinases and suppresses NF-κB signaling pathway in trophoblast cells

Leilei Wang

Papers

MicroRNA-204 suppresses trophoblast-like cell invasion by targeting matrix metalloproteinase-9.

Effect of Human Umbilical Cord Mesenchymal Stem Cell Transplantation in a Rat Model of Preeclampsia.

Therapeutic benefit of mesenchymal stem cells in pregnant rats with angiotensin receptor agonistic autoantibody-induced hypertension: Implications for immunomodulation and cytoprotection.

RNA interference-mediated silencing of laminin receptor 1 (LR1) suppresses migration and invasion and down-regulates matrix metalloproteinase (MMP)-2 and MMP-9 in trophoblast cells: implication in the pathogenesis of preeclampsia

RNA interference-mediated knockdown of Notch-1 inhibits migration and invasion, down-regulates matrix metalloproteinases and suppresses NF-κB signaling pathway in trophoblast cells