Preeclampsia Is Associated with Alterations in DNA Methylation of Genes Involved in Collagen Metabolism

Mousa, Ahmad A.; Cappello, Renato E.; Estrada-Gutiérrez, Guadalupe; Shukla, Juhi; Romero, Roberto; Strauss, Jerome F.; Walsh, Scott W.

doi:10.1016/j.ajpath.2012.06.019

Cited by 28 publications

(23 citation statements)

References 25 publications

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“…Hence, these factors might be contributing to poor migration and proliferation of the endothelial cells and poor development of new blood vessels. The observed high expression of MMP2 in maternal blood in preeclampsia is consistent with the documented high level of MMP2 in preeclamptic plasma (Myers et al 2005) and might have a role in regulating vascular tone, as highlighted by a recent study that suggested the role of MMP1 expression in vasoconstriction (Mousa et al 2012). Consistent with our results, high levels of TIMP1 and TIMP2 have been demonstrated in preeclamptic endothelial cells (Merchant et al 2004).…”

Section: Discussionsupporting

confidence: 80%

Imbalance between matrix metalloproteinases and their tissue inhibitors in preeclampsia and gestational trophoblastic diseases

Rahat¹,

Sharma²,

Bagga³

et al. 2016

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The invasion cascade exhibited by placental trophoblasts and cancerous cells bears many similarities, and it is attributed to extracellular matrix degradation mediated by matrix metalloproteinases (MMPs). Although proper and controlled invasion by trophoblasts into the maternal uterus is an essential requirement for maintenance of normal pregnancy, any abnormality in this phenomenon results in the development of invasion-related disorders such as gestational trophoblastic diseases (GTDs) and preeclampsia. We studied the epigenetic basis of differential expression of two placental MMPs (MMP2 and MMP9) and tissue inhibitors of metalloproteinases (TIMP2 and TIMP1) during normal gestation and invasion-related disorders, i.e., preeclampsia and GTDs. Our study suggests the association of H3K9/27me3 with differential expression of these MMPs and their inhibitors, which regulate the placental invasion during normal pregnancy, whereas no role of CpG methylation was observed in the differential expression of MMPs/TIMPs. Further, development of GTDs was associated with abnormally higher expression of these MMPs and lower levels of their inhibitors, whereas the reverse trends were observed for MMPs and their TIMPs in case of preeclampsia, in association with abnormal changes in H3K9/27me3. These results suggest the involvement of higher levels of MMPs in an aggressive invasive behavior depicted by GTDs, whereas lower levels of these MMPs in shallow and poor invasive phenotype associated with preeclampsia. Thus, our study shows the significance of a proper balance regulated by histone trimethylation between differential expression of MMPs and their TIMPs for maintaining normal pregnancy and its deregulation as a contributing factor for pathogenesis of invasive disorders during pregnancy.

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Section: Discussionsupporting

confidence: 80%

Imbalance between matrix metalloproteinases and their tissue inhibitors in preeclampsia and gestational trophoblastic diseases

Rahat¹,

Sharma²,

Bagga³

et al. 2016

Reproduction

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“…Matrix alterations in the maternal vasculature have recently been implicated in preeclampsia. MMP-1 was found to be hypomethylated in omental arteries from preeclamptic women, and 5-Aza treatment induced MMP-1 mRNA expression and protein secretion in cultured human vascular SMC [63]. …”

Section: Role Of Epigenetics In Regulating Smc Plasticitymentioning

confidence: 99%

Epigenetic regulation of smooth muscle cell plasticity

Liu

Leslie

Martin

2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

119

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Smooth muscle cells (SMC) are the major cell type in blood vessels. Their principle function in the body is to regulate blood flow and pressure through vessel wall contraction and relaxation. Unlike many other mature cell types in the adult body, SMC do not terminally differentiate but retain a remarkable plasticity. They have the unique ability to toggle between a differentiated and quiescent “contractile” state and a highly proliferative and migratory “synthetic” phenotype in response to environmental stresses. While there have been major advances in our understanding of SMC plasticity through the identification of growth factors and signals that can influence the SMC phenotype, how these regulate SMC plasticity remains unknown. To date, several key transcription factors and regulatory cis elements have been identified that play a role in modulating SMC state. The frontier in understanding the molecular mechanisms underlying SMC plasticity has now advanced to the level of epigenetics. This review will summarize the epigenetic regulation of SMC, highlighting the role of histone modification, DNA methylation, and our most recent identification of a DNA demethylation pathway in SMC that is pivotal in the regulation of the SMC phenotypic state. Many disorders are associated with smooth muscle dysfunction, including atherosclerosis, the major underlying cause of stroke and coronary heart disease, as well as transplant vasculopathy, aneurysm, asthma, hypertension, and cancer. An increased understanding of the major regulators of SMC plasticity will lead to the identification of novel target molecules that may, in turn, lead to novel drug discoveries for the treatment of these diseases.

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“…The alterations in DNA methylation of MMP8 gene were found in preeclampsia, a disease in which dizziness is one of the symptoms. Mousa et al [2012] showed that DNA hypomethylation significantly increased MMP-8 expression. The promoter regions of the MMP1 and MMP8 genes have reduced methylation in the omental arteries of preeclamptic women compared with those of normal pregnant women.…”

Section: Discussionmentioning

confidence: 99%

An Analysis of the Association between Epilepsy-Related Genes and Vertigo in the Polish Population

et al. 2018

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Considering the possibility of a common genetic background of vertigo and epilepsy, we genotyped an affected group of individuals with vertigo and an unaffected group, by studying 26 single-nucleotide polymorphisms (SNPs) in 14 genes which were previously reported to be of particular importance for epilepsy. Significant differences were found between the patients and the control group (χ² = 38.3, df = 3, p = 1.6 × 10^–7) for the frequencies of haplotypes consist ing of 2 SNPs located in chromosome 11 (rs1939012 and rs1783901 within genes MMP8 and SCN3B, respectively). The haplotype rs1939012:C-rs1783901:A, consisting of the minor-frequency alleles was found to be associated with a higher risk of vertigo (OR = 5.0143, 95% CI = 1.6991–14.7980, p = 0.0035). In contrast, the haplotype rs1939012:T-rs1783901:A showed a significant association with a decreased risk of the disease (OR = 0.0597, 95% CI = 0.0136–0.2620, p = 0.0002). Our results suggest that the SNPs rs1939012 and rs1783901 may play a potential role of gene regulation and/or epistasis in a complex etiology of vertigo.

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Preeclampsia Is Associated with Alterations in DNA Methylation of Genes Involved in Collagen Metabolism

Cited by 28 publications

References 25 publications

Imbalance between matrix metalloproteinases and their tissue inhibitors in preeclampsia and gestational trophoblastic diseases

Imbalance between matrix metalloproteinases and their tissue inhibitors in preeclampsia and gestational trophoblastic diseases

Epigenetic regulation of smooth muscle cell plasticity

An Analysis of the Association between Epilepsy-Related Genes and Vertigo in the Polish Population

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