Increased Serum Levels of Inflammatory Mediators and Low Frequency of Regulatory T Cells in the Peripheral Blood of Preeclamptic Mexican Women

Moreno-Eutímio, Mario Adán; Tovar-Rodríguez, José María; Vargas-Avila, Karina; Nieto-Velázquez, Nayeli Goreti; Frías-De-León, María Guadalupe; Sierra-Martínez, Mónica; Acosta-Altamirano, Gustavo

doi:10.1155/2014/413249

Cited by 38 publications

(35 citation statements)

References 39 publications

(46 reference statements)

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“…There is controversy with respect to the concentrations of these proteins in PE [21][22][23][24][25][26][27][28]. On the other hand, we observed that the maternal concentrations of VCAM-1 were higher in PE.…”

Section: Discussionmentioning

confidence: 61%

Placental Proinflammatory State and Maternal Endothelial Dysfunction in Preeclampsia

Valencia

Zárate

Saucedo

et al. 2018

Gynecol Obstet Invest

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Objective: To evaluate the placental and decidual gene expression and maternal and umbilical serum concentrations of tumor necrosis factor alpha, interleukin 6 (IL-6), IL-8, IL-10, IL-1 receptor antagonist (IL-1RA), intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (VCAM-1), along with the proinflammatory/anti-inflammatory cytokine ratios in women with preeclampsia (PE) vs. women with normal pregnancy (NP), and to analyze PE classified as early- (EO) and late-onset (LO). Methods: This cross-sectional study was performed with 50 women with PE (EO n = 30, LO n = 20) and 50 women with NP. Tissue gene expression levels were measured by real-time RT-PCR. Cytokines and adhesion molecules serum concentrations were measured by immunoassays. Results: In PE, placental expression of IL-10 and IL-1RA was lower, while placental IL-8/IL-1RA ratio and maternal concentrations of VCAM-1 were higher vs. NP. In EO, placental expression of IL-10 was lower, while placental IL-8/IL-10 and IL-8/IL-1RA ratios were higher than LO and NP. Maternal concentrations of IL-6 were higher in LO than EO and NP. Throughout PE, maternal VCAM-1 concentrations were higher vs. NP. No significant differences were observed in the decidual expression and umbilical concentrations of the markers between the groups. Conclusion: PE associates with a proinflammatory placental state; however, EO associates with a proinflammatory placental state, while LO associates with systemic maternal inflammation. Both subtypes associated with maternal endothelial dysfunction.

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Section: Discussionmentioning

confidence: 61%

Placental Proinflammatory State and Maternal Endothelial Dysfunction in Preeclampsia

Valencia

Zárate

Saucedo

et al. 2018

Gynecol Obstet Invest

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“…Circulating TNF-α levels are increased in PE compared with Norm-Preg women (Moreno-Eutimio et al, 2014; Pinheiro et al, 2015; Cakmak et al, 2016), although the placental levels of TNF-α may not be different in PE versus normal pregnancy (Peixoto et al, 2016). LIGHT, a TNF superfamily member, is also increased in PE and may contribute to placental damage and ischemia (Wang et al, 2014).…”

Section: Circulating Bioactive Factors In Preeclampsiamentioning

confidence: 95%

“…IL-6 is a pro-inflammatory cytokine that may also be elevated in PE (Ramma et al, 2012; Moreno-Eutimio et al, 2014). RUPP rats show increased plasma levels and higher CD4 + T cell production of IL-6 (Wallace et al, 2011; Cornelius et al, 2015), and infusion of IL-6 leads to HTN and proteinuria in pregnant rats (Lamarca et al, 2011).…”

Section: Circulating Bioactive Factors In Preeclampsiamentioning

confidence: 99%

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

Possomato-Vieira

Khalil

2016

Advances in Pharmacology

185

117

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Preeclampsia is a pregnancy-related disorder characterized by hypertension, and could lead to maternal and fetal morbidity and mortality. Although the causative factors and pathophysiological mechanisms are unclear, endothelial dysfunction is a major hallmark of preeclampsia. Clinical tests and experimental research have suggested that generalized endotheliosis in the systemic, renal, cerebral and hepatic circulation could decrease endothelium-derived vasodilators such as nitric oxide, prostacyclin and hyperpolarization factor and increase vasoconstrictors such as endothelin-1 and thromboxane A2, leading to increased vasoconstriction, hypertension and other manifestation of preeclampsia. In search for the upstream mechanisms that could cause endothelial dysfunction, certain genetic, demographic and environmental risk factors have been suggested to cause abnormal expression of uteroplacental integrins, cytokines and matrix metalloproteinases, leading to decreased maternal tolerance, apoptosis of invasive trophoblast cells, inadequate spiral arteries remodeling, reduced uterine perfusion pressure (RUPP), and placental ischemia/hypoxia. RUPP may cause imbalance between the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the pro-angiogenic factors vascular endothelial growth factor and placental growth factor, or stimulate the release of other circulating bioactive factors such as inflammatory cytokines, hypoxia-inducible factor-1, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors could then target endothelial cells and cause generalized endothelial dysfunction. Therapeutic options are currently limited, but understanding the factors involved in endothelial dysfunction could help design new approaches for prediction and management of preeclampsia.

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“…Placental ischemia may enhance the release of inflammatory cytokines such as tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) [96–98]. Circulating TNFα levels are increased in preeclamptic vs normal Preg women [108–110], and the plasma levels and CD4 + T cell production of TNFα are increased in RUPP vs Preg rats [98, 111, 112]. TNF-α may modify the expression of adhesion molecules in placental vessels [98] and may contribute to abnormal MMP production in preeclampsia.…”

Section: Discussionmentioning

confidence: 99%

Decreased homodimerization and increased TIMP-1 complexation of uteroplacental and uterine arterial matrix metalloproteinase-9 during hypertension-in-pregnancy

Chen

Ren

Zhu

et al. 2017

Biochemical Pharmacology

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Preeclampsia is a complication of pregnancy manifested as hypertension-in-pregnancy (HTN-Preg) and often intrauterine growth restriction (IUGR). Placental ischemia could be an initiating event, but the molecular mechanisms are unclear. To test the hypothesis that dimerization of matrix metalloproteinases (MMPs) plays a role in HTN-Preg and IUGR, the levels/activity of MMP-9, tissue inhibitor of metalloproteinase (TIMP-1), and their dimerization forms were measured in the placenta, uterus, and uterine artery of normal pregnant (Preg) rats and a rat model of reduced uteroplacental perfusion pressure (RUPP). Consistent with our previous report, blood pressure (BP) was higher, pup weight was lower, and gelatin zymography showed different gelatinolytic activity for pro-MMP-9, MMP-9, pro-MMP-2 and MMP-2 in RUPP vs Preg rats. Careful examination of the zymograms showed additional bands at 200 and 135 kDa. Western blots with MMP-9 antibody suggested that the 200 kDa band was a MMP-9 homodimer. Western blots with TIMP-1 antibody as well as reverse zymography suggested that the 135 kDa band was a MMP-9/TIMP-1 complex. The protein levels and gelatinase activity of MMP-9 homodimer were decreased while MMP-9/TIMP-1 complex was increased in placenta, uterus and uterine artery of RUPP vs Preg rats. The epidermal growth factor (EGF) receptor blocker erlotinib and protein kinase C (PKC) inhibitor bisindolylmaleimide decreased MMP-9 homodimer and increased MMP-9/TIMP-1 complex in placenta, uterus and uterine artery of Preg rats. EGF and the PKC activator phorbol-12,13-dibutyrate (PDBu) reversed the decreases in MMP-9 homodimer and the increases in MMP-9/TIMP-1 complex in tissues of RUPP rats. Thus, the increased BP and decreased pup weight in placental ischemia model of HTN-Preg are associated with a decrease in MMP-9 homodimer and an increase in MMP-9/TIMP-1 complex in placenta, uterus, and uterine artery, which together would cause a net decrease in MMP-9 activity and reduce uteroplacental and vascular remodeling in the setting of HTN-Preg and IUGR. Enhancing EGFR/PKC signaling may reverse the MMP-9 unfavorable dimerization patterns and thereby promote uteroplacental and vascular remodeling in preeclampsia.

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Increased Serum Levels of Inflammatory Mediators and Low Frequency of Regulatory T Cells in the Peripheral Blood of Preeclamptic Mexican Women

Cited by 38 publications

References 39 publications

Placental Proinflammatory State and Maternal Endothelial Dysfunction in Preeclampsia

Placental Proinflammatory State and Maternal Endothelial Dysfunction in Preeclampsia

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

Decreased homodimerization and increased TIMP-1 complexation of uteroplacental and uterine arterial matrix metalloproteinase-9 during hypertension-in-pregnancy

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