Matrix metalloproteinase multiplex screening identifies increased MMP-2 urine concentrations in women predicted to develop preeclampsia

Martínez‐Fierro, Margarita L.; Perez-Favila, Aurelio; Espinoza-Juarez, Marcela A.; Ávila-Carrasco, Lorena; Delgado‐Enciso, Iván; Ortiz-Castro, Yolanda; Cardenas-Vargas, Edith; Cid-Baez, Miguel A; Cervantes-Kardasch, Victor Hugo; Rodríguez‐Sánchez, Iram P.; Badillo-Almaraz, Jose I.; Castañeda‐Miranda, Rodrigo; Solís-Sánchez, Luis Octavio; Ortiz-Rodríguez, J.M.

doi:10.1080/1354750x.2017.1279214

Cited by 13 publications

(9 citation statements)

References 45 publications

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“…Although it is still unclear in the context of hypertension in pregnancy and preeclampsia [28], it is possible that upregulated activity of MMPs also contribute to the increased concentrations of vasoconstrictors and reduced concentrations of vasodilators [58,59,60,61]. Previous studies suggest that MMPs activity imbalance apparently generates vasoconstrictors and degrades vasodilators that may promote vasoconstriction and cause endothelial dysfunction, including in the preeclampsia [62].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, few clinical studies have evaluated the role of MMP-2 and MMP-9 in the pathophysiology of preeclampsia. In this regard, it was demonstrated increased MMP-2 levels in urine of preeclamptic women [28] and increases MMP-2 levels in aminiotic fluid of women who subsequently develop preeclampsia [67]. The same authors examined pro-MMP-9 levels in normal amniotic fluid, but zymogram wells loaded with preeclamptic amniotic fluid did not present any MMP-9 bands [67].…”

Section: Discussionmentioning

confidence: 99%

“…Also, other authors reported increases in activity of MMP-2 and MMP-9 in the uterus and aorta during middle and late pregnancy stages, but decreases in placental activity of these two gelatinases were observed in late compared to middle pregnancy stages in animals [24,25]. Furthermore, in hypertensive disorders of pregnancy, excessive gelatinolytic activity of MMP-2 and MMP-9 in plasma [26,27], and increases in MMP-2 in urine [28] have been found in women. Of note, these earlier studies have focused on the end of pregnancy, however, considering the potential role of NO to downregulate the MMP-2 and MMP-9 [29,30,31,32,33,34], we hypothesized that reductions in NO bioavailability caused by Nω-Nitro-L-arginine methyl ester (L-NAME) [35,36] could increase the activity of MMPs throughout pregnancy stages, since L-NAME-induced hypertensive pregnancy causes fetal-placental growth restriction because of decreases in utero-placental perfusion, which is the result of aberrant vascular remodeling in the utero-placental circulation [37,38].…”

Section: Introductionmentioning

confidence: 99%

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Reductions of Circulating Nitric Oxide are Followed by Hypertension during Pregnancy and Increased Activity of Matrix Metalloproteinases-2 and -9 in Rats

Nascimento

Possomato-Vieira

Bonacio

et al. 2019

Cells

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Hypertensive pregnancy has been associated with reduced nitric oxide (NO), bioavailability, and increased activity of matrix metalloproteinases (MMPs). However, it is unclear if MMPs activation is regulated by NO during pregnancy. To this end, we examined activity of MMP-2 and MMP-9 in plasma, placenta, uterus and aorta, NO bioavailability, oxidative stress, systolic blood pressure (SBP), and fetal-placental development at the early, middle, and late pregnancy stages in normotensive and Nω-Nitro-L-arginine methyl-ester (L-NAME)-induced hypertensive pregnancy in rats. Reduced MMP-2 activity in uterus, placenta, and aorta and reduced MMP-9 activity in plasma and placenta with concomitant increased NO levels were found in normotensive pregnant rats. By contrast, increased MMP-2 activity in uterus, placenta, and aorta, and increased MMP-9 activity in plasma and placenta with concomitant reduced NO levels were observed in hypertensive pregnant rats. Also, elevated oxidative stress was displayed by hypertensive pregnant rats at the middle and late stages. These findings in the L-NAME-treated pregnant rats were also followed by increases in SBP and associated with fetal growth restrictions at the middle and late pregnancy stages. We concluded that NO bioavailability may regulate MMPs activation during normal and hypertensive pregnancy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reductions of Circulating Nitric Oxide are Followed by Hypertension during Pregnancy and Increased Activity of Matrix Metalloproteinases-2 and -9 in Rats

Nascimento

Possomato-Vieira

Bonacio

et al. 2019

Cells

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“…The urine concentration of MMP-7 in patients who subsequently developed preeclampsia did not differ from those with a normal pregnancy, but the study could not differentiate between patients who subsequently developed early- and late-onset preeclampsia [168]. …”

Section: Discussionmentioning

confidence: 99%

The prediction of late-onset preeclampsia: Results from a longitudinal proteomics study

et al. 2017

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BackgroundLate-onset preeclampsia is the most prevalent phenotype of this syndrome; nevertheless, only a few biomarkers for its early diagnosis have been reported. We sought to correct this deficiency using a high through-put proteomic platform.MethodsA case-control longitudinal study was conducted, including 90 patients with normal pregnancies and 76 patients with late-onset preeclampsia (diagnosed at ≥34 weeks of gestation). Maternal plasma samples were collected throughout gestation (normal pregnancy: 2–6 samples per patient, median of 2; late-onset preeclampsia: 2–6, median of 5). The abundance of 1,125 proteins was measured using an aptamers-based proteomics technique. Protein abundance in normal pregnancies was modeled using linear mixed-effects models to estimate mean abundance as a function of gestational age. Data was then expressed as multiples of-the-mean (MoM) values in normal pregnancies. Multi-marker prediction models were built using data from one of five gestational age intervals (8–16, 16.1–22, 22.1–28, 28.1–32, 32.1–36 weeks of gestation). The predictive performance of the best combination of proteins was compared to placental growth factor (PIGF) using bootstrap.Results1) At 8–16 weeks of gestation, the best prediction model included only one protein, matrix metalloproteinase 7 (MMP-7), that had a sensitivity of 69% at a false positive rate (FPR) of 20% (AUC = 0.76); 2) at 16.1–22 weeks of gestation, MMP-7 was the single best predictor of late-onset preeclampsia with a sensitivity of 70% at a FPR of 20% (AUC = 0.82); 3) after 22 weeks of gestation, PlGF was the best predictor of late-onset preeclampsia, identifying 1/3 to 1/2 of the patients destined to develop this syndrome (FPR = 20%); 4) 36 proteins were associated with late-onset preeclampsia in at least one interval of gestation (after adjustment for covariates); 5) several biological processes, such as positive regulation of vascular endothelial growth factor receptor signaling pathway, were perturbed; and 6) from 22.1 weeks of gestation onward, the set of proteins most predictive of severe preeclampsia was different from the set most predictive of the mild form of this syndrome.ConclusionsElevated MMP-7 early in gestation (8–22 weeks) and low PlGF later in gestation (after 22 weeks) are the strongest predictors for the subsequent development of late-onset preeclampsia, suggesting that the optimal identification of patients at risk may involve a two-step diagnostic process.

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“…Urine samples from healthy and preeclamptic pregnancies were analyzed in a study that was carried out in order to predict the risk of developing preeclampsia at three different stages of early pregnancy (12, 16 and 20 gestational week). From a set of nine MMPs evaluated, only MMP-2 was found to be significantly higher at 12 and 16 weeks [ 48 ]. In a different study, 14 biomarkers for preeclampsia, including MMP-2 and MMP-9, were evaluated in urine samples.…”

Section: Mmps As New Biomarkers and Potential Biological Targets Imentioning

confidence: 99%

New Insights into the Role of Matrix Metalloproteinases in Preeclampsia

Sosa

Flores-Pliego

Espejel-Núñez

et al. 2017

IJMS

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Preeclampsia is a severe pregnancy complication globally, characterized by poor placentation triggering vascular dysfunction. Matrix metalloproteinases (MMPs) exhibit proteolytic activity implicated in the efficiency of trophoblast invasion to the uterine wall, and a dysregulation of these enzymes has been linked to preeclampsia. A decrease in MMP-2 and MMP-9 interferes with the normal remodeling of spiral arteries at early pregnancy stages, leading to the initial pathophysiological changes observed in preeclampsia. Later in pregnancy, an elevation in MMP-2 and MMP-9 induces abnormal release of vasoactive factors conditioning hypertension. Although these two enzymes lead the scene, other MMPs like MMP-1 and MMP-14 seem to have a role in this pathology. This review gathers published recent evidence about the implications of different MMPs in preeclampsia, and the potential use of these enzymes as emergent biomarkers and biological therapeutic targets, focusing on studies involving human subjects.

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Matrix metalloproteinase multiplex screening identifies increased MMP-2 urine concentrations in women predicted to develop preeclampsia

Abstract: Increased urinary concentration of MMP-2 at 12 and 16 weeks of gestation predicted an increased risk of developing preeclampsia in the study population.

Cited by 13 publications

References 45 publications

Reductions of Circulating Nitric Oxide are Followed by Hypertension during Pregnancy and Increased Activity of Matrix Metalloproteinases-2 and -9 in Rats

Reductions of Circulating Nitric Oxide are Followed by Hypertension during Pregnancy and Increased Activity of Matrix Metalloproteinases-2 and -9 in Rats

The prediction of late-onset preeclampsia: Results from a longitudinal proteomics study

New Insights into the Role of Matrix Metalloproteinases in Preeclampsia

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