The Effects of Preeclampsia and Oxygen Environment on Endothelial Release of Matrix Metalloproteinase‐2

Merchant, Shaila J.; Narumiya, Hisao; Zhang, Yunlong; Guilbert, Larry J.; Davidge, Sandra T.

doi:10.1081/prg-120028281

Cited by 35 publications

(24 citation statements)

References 52 publications

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“…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). High expression levels of TIMP2 and TIMP1 in preeclampsia might be further decreasing the activities of already compromised levels of MMP2 and MMP1, respectively, hence leading to decreased invasion of uterine vasculature.…”

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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“…The endothelial nature of these cells was confirmed by staining for the endothelium-specific marker, von Willebrand’s factor (data not shown). Our laboratory has published extensively using HUVECs as a model for the vascular endothelium [40,41,42,43,44]. …”

Section: Methodsmentioning

confidence: 99%

Estradiol Modulates Tumor Necrosis Factor-Induced Endothelial Inflammation: Role of Tumor Necrosis Factor Receptor 2

Chakrabarti¹,

Davidge²

2012

J Vasc Res

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The sex hormone estradiol (E₂) appears to mediate both anti-atherogenic and pro-inflammatory effects in premenopausal women, suggesting a complex immunomodulatory role. Tumor necrosis factor (TNF) is a key pro-inflammatory cytokine involved in the pathogenesis of atherosclerosis and other inflammatory diseases. Alterations at the TNF receptors (TNFRs) and their downstream signaling/transcriptional pathways can affect inflammatory responses. Given this background, we hypothesized that chronic E₂ exposure would alter endothelial inflammatory response involving modulation at the levels of TNFRs and signaling pathways. HUVECs were used as the model system. Pre-treatment with E₂ did not significantly alter TNF-induced upregulation of pro-inflammatory molecules ICAM-1 (3–6 times) and VCAM-1 (5–7 times). However, pharmacological inhibition of transcriptional pathways suggested a partial shift from NF-ĸB (from 97 to 64%) towards the JNK/AP-1 pathway in ICAM-1 upregulation on E₂ treatment. In contrast, VCAM-1 expression remained NF-ĸB dependent in both control (∼96%) and E₂ treated (∼85%) cells. The pro-inflammatory TNF effects were mediated by TNFR1. Interestingly, E₂ pre-treatment increased TNFR2 levels in these cells. Concomitant TNFR2 activation (but not TNFR1 activation alone) led to the shift towards JNK/AP-1-mediated ICAM-1 upregulation in E₂-treated cells, suggesting the effects of chronic E₂ to be dependent on TNFR2 signaling.

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“…Studies suggest that plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 are higher in HTN-Preg than Norm-Preg women (Merchant et al2004; Tayebjee et al2004). Other studies have shown that the levels of MMP-2 and -9 in decidua cells are not elevated in PE (Huisman et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Vascular and Cellular Calcium in Normal and Hypertensive Pregnancy

Adamová¹,

Ozkan²,

Khalil³

2009

CCP

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Normal pregnancy is associated with significant hemodynamic changes in the cardiovascular system in order to meet the metabolic demands of mother and fetus. These changes include increased cardiac output, decreased vascular resistance, and vascular remodeling in the uterine and systemic circulation. Preeclampsia (PE) is a major complication of pregnancy characterized by proteinuria and hypertension. Several risk factors have been implicated in the pathogenesis of PE including genetic and dietary factors. Ca 2+ is an essential dietary element and an important regulator of many cellular processes including vascular function. The importance of adequate dietary Ca 2+ intake during pregnancy is supported by many studies. Pregnancy-associated changes in Ca 2+ metabolism and plasma Ca 2+ have been observed. During pregnancy, changes in intracellular free Ca 2+ concentration ([Ca 2+ ] i ) have been described in red blood cells, platelets and immune cells. Also, during pregnancy, an increase in [Ca 2+ ] i in endothelial cells (EC) stimulates the production of vasodilator substances such as nitric oxide and prostacyclin. Normal pregnancy is also associated with decreased vascular smooth muscle (VSM) [Ca 2+ ] i and possibly the Ca 2+ -sensitization pathways of VSM contraction including protein kinase C, Rho-kinase, and mitogen-activated protein kinase. Ca 2+ -dependent matrix metalloproteinases could also promote extracellular matrix degradation and vascular remodeling during pregnancy. Disruption in the balance between dietary, plasma and vascular cell Ca 2+ may be responsible for some of the manifestation of PE including procoagulation, decreased vasodilation, and increased vasoconstriction and vascular resistance. The potential benefits of Ca 2+ supplements during pregnancy, and the use of modulators of vascular Ca 2+ to reduce the manifestations of PE in susceptible women remain an important area for experimental and clinical research.

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The Effects of Preeclampsia and Oxygen Environment on Endothelial Release of Matrix Metalloproteinase‐2

Cited by 35 publications

References 52 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

Estradiol Modulates Tumor Necrosis Factor-Induced Endothelial Inflammation: Role of Tumor Necrosis Factor Receptor 2

Vascular and Cellular Calcium in Normal and Hypertensive Pregnancy

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