New Insights into the Role of Matrix Metalloproteinases in Preeclampsia

Sosa, Salvador Espino Y; Flores-Pliego, Arturo; Espejel-Núñez, Aurora; Medina-Bastidas, Diana; Vadillo-Ortega, Felipe; Zaga‐Clavellina, Veronica; Estrada-Gutiérrez, Guadalupe

doi:10.3390/ijms18071448

Cited by 85 publications

(51 citation statements)

References 68 publications

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“…*P Ͻ 0.05, **P Ͻ 0.01 vs. control group; #P Ͻ 0.05, ##P Ͻ 0.01 vs. vector group. normal remodeling of spiral arteries at early pregnancy stages, resulting in the initial pathophysiological changes observed in PE (4). Therefore, in this study the increased HTR8/SVneo cell invasion by ANXA4 overexpression may be due to ANXA4 overexpression-induced increased MMP2/9 expression.…”

Section: Discussionmentioning

confidence: 61%

ANXA4 promotes trophoblast invasion via the PI3K/Akt/eNOS pathway in preeclampsia

Sui

Qiu

et al. 2019

American Journal of Physiology-Cell Physiology

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The inadequate trophoblast invasion is associated with the development of preeclampsia (PE). Considering that annexin A4 (ANXA4) enhances tumor invasion, we aimed to explore the functional role of ANXA4 in trophoblast cells and to examine the underlying mechanism. ANXA4 expression in PE placentas was analyzed using immunohistochemistry and Western blotting. Cell proliferation, invasion, and apoptosis were determined using a MTT assay, Transwell assay, and flow cytometry, respectively. The expression levels of matrix metalloproteinase (MMP)-2, MMP-9, phosphoinositide 3-kinase (PI3K), Akt, phosphorylated (p)-Akt, and phosphorylated endothelial nitric oxide synthase (p-eNOS) were detected by Western blotting. Placentas were prepared for pathological examination using hematoxylin and eosin staining and apoptosis determination using the TUNEL method. Expression of ANXA4, PI3K, p-Akt and p-eNOS was downregulated in human PE placentas and PE placenta-derived extravillous cytotrophoblasts (EVCTs). Furthermore, ANXA4 overexpression promoted cell proliferation and invasion, inhibited cell apoptosis, and upregulated protein expression of PI3K, p-Akt, and p-eNOS in human trophoblast cells HTR-8/SVneo and JEG-3. By contrast, ANXA4 knockdown exerted the opposite effects. Furthermore, inhibition of the PI3K/Akt pathway by LY294002 abrogated the ANXA4 overexpression-mediated effects on trophoblast behavior. Furthermore, eNOS knockdown abrogated the ANXA4 overexpression-induced promotion of cell invasion and MMP2/9 expression. Additionally, in N-nitro-l-arginine methyl ester (l-NAME)-induced PE rats, ANXA4 overexpression alleviated PE progression, accompanied by an increase in expression of PI3K, p-Akt, and p-eNOS in rat placentas. Our findings demonstrate that ANXA4 expression is downregulated in PE. ANXA4 may promote trophoblast invasion via the PI3K/Akt/eNOS pathway.

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Section: Discussionmentioning

confidence: 61%

ANXA4 promotes trophoblast invasion via the PI3K/Akt/eNOS pathway in preeclampsia

Sui

Qiu

et al. 2019

American Journal of Physiology-Cell Physiology

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“…1 E ). Matrix metalloproteases (MMPs) play crucial roles in the extracellular matrix remodeling of the placenta and pregnancy complications including preterm birth and preeclampsia ( 21 , 22 ). Furthermore, we observed increased placental MMP-9 expression in IAV-infected dams when compared to uninfected controls ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Influenza A virus causes maternal and fetal pathology via innate and adaptive vascular inflammation in mice

Liong

Oseghale

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Influenza A virus (IAV) infection during pregnancy causes severe maternal and perinatal complications, despite a lack of vertical transmission of IAV across the placenta. Here, we demonstrate a significant alteration in the maternal vascular landscape that underpins the maternal and downstream fetal pathology to IAV infection in mice. In IAV infection of nonpregnant mice, the local lung inflammatory response was contained to the lungs and was self-resolving, whereas in pregnant mice, virus dissemination to major maternal blood vessels, including the aorta, resulted in a peripheral "vascular storm," with elevated proinflammatory and antiviral mediators and the influx of Ly6Clow and Ly6Chigh monocytes, plus neutrophils and T cells. This vascular storm was associated with elevated levels of the adhesion molecules ICAM and VCAM and the pattern-recognition receptors TLR7 and TLR9 in the vascular wall, resulting in profound vascular dysfunction. The sequalae of this IAV-driven vascular storm included placental growth retardation and intrauterine growth restriction, evidence of placental and fetal brain hypoxia, and increased circulating cell free fetal DNA and soluble Flt1. In contrast, IAV infection in nonpregnant mice caused no obvious alterations in endothelial function or vascular inflammation. Therefore, IAV infection during pregnancy drives a significant systemic vascular alteration in pregnant dams, which likely suppresses critical blood flow to the placenta and fetus. This study in mice provides a fundamental mechanistic insight and a paradigm into how an immune response to a respiratory virus, such as IAV, is likely to specifically drive maternal and fetal pathologies during pregnancy.

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“…This family of proteins presents abnormal concentration and behavior in placental diseases such as PE [200], placenta accreta and placenta percreta [201,202]. This has been recently reviewed for preeclampsia [203]. A decreased level of MMP-2 and MMP-9 reduces the remodeling of spiral arteries in early gestation.…”

Section: Epigenetic Alterations In Preeclampsiamentioning

confidence: 99%

The Role of Epigenetics in Placental Development and the Etiology of Preeclampsia

Apicella

Ruano

Méhats

et al. 2019

IJMS

113

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In this review, we comprehensively present the function of epigenetic regulations in normal placental development as well as in a prominent disease of placental origin, preeclampsia (PE). We describe current progress concerning the impact of DNA methylation, non-coding RNA (with a special emphasis on long non-coding RNA (lncRNA) and microRNA (miRNA)) and more marginally histone post-translational modifications, in the processes leading to normal and abnormal placental function. We also explore the potential use of epigenetic marks circulating in the maternal blood flow as putative biomarkers able to prognosticate the onset of PE, as well as classifying it according to its severity. The correlation between epigenetic marks and impacts on gene expression is systematically evaluated for the different epigenetic marks analyzed.

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New Insights into the Role of Matrix Metalloproteinases in Preeclampsia

Cited by 85 publications

References 68 publications

ANXA4 promotes trophoblast invasion via the PI3K/Akt/eNOS pathway in preeclampsia

ANXA4 promotes trophoblast invasion via the PI3K/Akt/eNOS pathway in preeclampsia

Influenza A virus causes maternal and fetal pathology via innate and adaptive vascular inflammation in mice

The Role of Epigenetics in Placental Development and the Etiology of Preeclampsia

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