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Matrix metalloproteinase-9 deficiency phenocopies features of preeclampsia and intrauterine growth restriction.

ABSTRACT: The pregnancy complication preeclampsia (PE), which occurs in approximately 3% to 8% of human pregnancies, is characterized by placental pathologies that can lead to significant fetal and maternal morbidity and mortality. Currently, the only known cure is delivery of the placenta. As the etiology of PE remains unknown, it is vital to find models to study this common syndrome. Here we show that matrix metalloproteinase-9 (MMP9) deficiency causes physiological and placental abnormalities in mice, which mimic features of PE. As with the severe cases of this syndrome, which commence early in gestation, MMP9-null mouse embryos exhibit deficiencies in trophoblast differentiation and invasion shortly after implantation, along with intrauterine growth restriction or embryonic death. Reciprocal embryo transfer experiments demonstrated that embryonic MMP9 is a major contributor to normal implantation, but maternal MMP9 also plays a role in embryonic trophoblast development. Pregnant MMP9-null mice bearing null embryos exhibited clinical features of PE as VEGF dysregulation and proteinuria accompanied by preexisting elevated blood pressure and kidney pathology. Thus, our data show that fetal and maternal MMP9 play a role in the development of PE and establish the MMP9-null mice as a much-needed model to study the clinical course of this syndrome.

SUBMITTER: Plaks V

PROVIDER: S-EPMC3704020 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Matrix metalloproteinase-9 deficiency phenocopies features of preeclampsia and intrauterine growth restriction.

Plaks Vicki V Rinkenberger Julie J Dai Joanne J Flannery Margaret M Sund Malin M Kanasaki Keizo K Ni Wei W Kalluri Raghu R Werb Zena Z

Proceedings of the National Academy of Sciences of the United States of America 20130617 27

The pregnancy complication preeclampsia (PE), which occurs in approximately 3% to 8% of human pregnancies, is characterized by placental pathologies that can lead to significant fetal and maternal morbidity and mortality. Currently, the only known cure is delivery of the placenta. As the etiology of PE remains unknown, it is vital to find models to study this common syndrome. Here we show that matrix metalloproteinase-9 (MMP9) deficiency causes physiological and placental abnormalities in mice, ...[more]

PMID: 23776237

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Project description:BACKGROUND:Preeclampsia and intrauterine growth restriction are placental dysfunction-related disorders (PDDs) that require a referral decision be made within a certain time period. An appropriate prediction model should be developed for these diseases. However, previous models did not demonstrate robust performances and/or they were developed from datasets with highly imbalanced classes. OBJECTIVE:In this study, we developed a predictive model of PDDs by machine learning that uses features at 24-37 weeks' gestation, including maternal characteristics, uterine artery (UtA) Doppler measures, soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and placental growth factor (PlGF). METHODS:A public dataset was taken from a prospective cohort study that included pregnant women with PDDs (66/95, 69%) and a control group (29/95, 31%). Preliminary selection of features was based on a statistical analysis using SAS 9.4 (SAS Institute). We used Weka (Waikato Environment for Knowledge Analysis) 3.8.3 (The University of Waikato, Hamilton, NZ) to automatically select the best model using its optimization algorithm. We also manually selected the best of 23 white-box models. Models, including those from recent studies, were also compared by interval estimation of evaluation metrics. We used the Matthew correlation coefficient (MCC) as the main metric. It is not overoptimistic to evaluate the performance of a prediction model developed from a dataset with a class imbalance. Repeated 10-fold cross-validation was applied. RESULTS:The classification via regression model was chosen as the best model. Our model had a robust MCC (.93, 95% CI .87-1.00, vs .64, 95% CI .57-.71) and specificity (100%, 95% CI 100-100, vs 90%, 95% CI 90-90) compared to each metric of the best models from recent studies. The sensitivity of this model was not inferior (95%, 95% CI 91-100, vs 100%, 95% CI 92-100). The area under the receiver operating characteristic curve was also competitive (0.970, 95% CI 0.966-0.974, vs 0.987, 95% CI 0.980-0.994). Features in the best model were maternal weight, BMI, pulsatility index of the UtA, sFlt-1, and PlGF. The most important feature was the sFlt-1/PlGF ratio. This model used an M5P algorithm consisting of a decision tree and four linear models with different thresholds. Our study was also better than the best ones among recent studies in terms of the class balance and the size of the case class (66/95, 69%, vs 27/239, 11.3%). CONCLUSIONS:Our model had a robust predictive performance. It was also developed to deal with the problem of a class imbalance. In the context of clinical management, this model may improve maternal mortality and neonatal morbidity and reduce health care costs.

Project description:Preeclampsia and intrauterine growth restriction are two separate disease entities that, according to numerous reports, share the same pathogenesis. In both, angiogenesis disorders and generalized inflammation are the dominant symptoms. In this study, we hypothesized that both diseases demonstrate the same profile in early preeclampsia, late preeclampsia, and intrauterine growth restriction patients, with the only difference being the degree of exacerbation of lesions. One hundred sixty-seven patients were enrolled in the study and divided into four groups: early preeclampsia, late preeclampsia, and intrauterine growth restriction groups, and one control group. Concentrations of the angiogenesis and inflammatory markers soluble fms-like tyrosine kinase receptor 1, placental growth factor, high-sensitivity C-reactive protein, and interleukin-6 were determined, and the behavior of these markers and correlations among them were studied. Higher concentrations of soluble fms-like tyrosine kinase receptor 1, high-sensitivity C-reactive protein, and interleukin-6 and a lower concentration of placental growth factor were observed in the study groups compared with the control group. No differences in concentrations of the studied markers were found among the study groups but significant correlations were observed. The higher values for the angiogenesis and inflammatory markers both in preeclampsia patients and patients with intrauterine growth restriction of placental origin compared with the control group suggest the existence of the same underlying disorders in the development of these pathologies. The observed mutual correlations for disordered angiogenesis and inflammatory markers are suggestive of a mutual relationship between these processes in the development of pathologies evolving secondary to placental ischemia. The same lesion profile was observed for both preeclampsia and 'placental' intrauterine growth restriction patients, which could be used in developing common diagnostic criteria for pregnant patients.

Project description:ObjectivesPreeclampsia is divided into early-onset (delivery before 34 weeks of gestation) and late-onset (delivery at or after 34 weeks) subtypes, which may rise from different etiopathogenic backgrounds. Early-onset disease is associated with placental dysfunction. Late-onset disease develops predominantly due to metabolic disturbances, obesity, diabetes, lipid dysfunction, and inflammation, which affect endothelial function. Our aim was to use cluster analysis to investigate clinical factors predicting the onset and severity of preeclampsia in a cohort of women with known clinical risk factors.MethodsWe recruited 903 pregnant women with risk factors for preeclampsia at gestational weeks 12+0-13+6. Each individual outcome diagnosis was independently verified from medical records. We applied a Bayesian clustering algorithm to classify the study participants to clusters based on their particular risk factor combination. For each cluster, we computed the risk ratio of each disease outcome, relative to the risk in the general population.ResultsThe risk of preeclampsia increased exponentially with respect to the number of risk factors. Our analysis revealed 25 number of clusters. Preeclampsia in a previous pregnancy (n = 138) increased the risk of preeclampsia 8.1 fold (95% confidence interval (CI) 5.7-11.2) compared to a general population of pregnant women. Having a small for gestational age infant (n = 57) in a previous pregnancy increased the risk of early-onset preeclampsia 17.5 fold (95%CI 2.1-60.5). Cluster of those two risk factors together (n = 21) increased the risk of severe preeclampsia to 23.8-fold (95%CI 5.1-60.6), intermediate onset (delivery between 34+0-36+6 weeks of gestation) to 25.1-fold (95%CI 3.1-79.9) and preterm preeclampsia (delivery before 37+0 weeks of gestation) to 16.4-fold (95%CI 2.0-52.4). Body mass index over 30 kg/m2 (n = 228) as a sole risk factor increased the risk of preeclampsia to 2.1-fold (95%CI 1.1-3.6). Together with preeclampsia in an earlier pregnancy the risk increased to 11.4 (95%CI 4.5-20.9). Chronic hypertension (n = 60) increased the risk of preeclampsia 5.3-fold (95%CI 2.4-9.8), of severe preeclampsia 22.2-fold (95%CI 9.9-41.0), and risk of early-onset preeclampsia 16.7-fold (95%CI 2.0-57.6). If a woman had chronic hypertension combined with obesity, gestational diabetes and earlier preeclampsia, the risk of term preeclampsia increased 4.8-fold (95%CI 0.1-21.7). Women with type 1 diabetes mellitus had a high risk of all subgroups of preeclampsia.ConclusionThe risk of preeclampsia increases exponentially with respect to the number of risk factors. Early-onset preeclampsia and severe preeclampsia have different risk profile from term preeclampsia.

Dataset Information

Matrix metalloproteinase-9 deficiency phenocopies features of preeclampsia and intrauterine growth restriction.

Publications

Matrix metalloproteinase-9 deficiency phenocopies features of preeclampsia and intrauterine growth restriction.

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