A Role of sFlt-1 in Oxidative Stress and Apoptosis in Human and Mouse Pre-Eclamptic Trophoblasts1

Jiang, Ziyan; Zou, Yanfen; Ge, Zhiping; Zuo, Qiang; Huang, Shi; Sun, Lichao

doi:10.1095/biolreprod.114.126227

Cited by 43 publications

(28 citation statements)

References 33 publications

(40 reference statements)

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“…Other animal models of HTN-Preg show increased or unchanged circulating levels of sFlt-1 (Agunanne et al, 2010; Ramesar et al, 2011; Sunderland et al, 2011; Siddiqui et al, 2013; Bobek et al, 2015; Gillis et al, 2015). Importantly, pregnant rats treated with exogenous sFlt-1 develop HTN, proteinuria, marked glomerular endotheliosis with occlusion of renal capillaries and focal fibrin deposition in glomerular cells (Maynard et al, 2003; Holwerda et al, 2014; Jiang et al, 2015). Also, mice treated with sFlt-1 show an increase in the vascular response to ET-1 (Amraoui et al, 2014).…”

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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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

View full text Add to dashboard Cite

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“…Mitochondrial activity is essential in pregnancy because it sustains the metabolic activity of the placenta throughout gestation (LaMarca et al, 2008 ). Recently, a potential association between increased soluble anti-angiogenic factors levels and mitochondrial dysfunction has been suggested (Jiang et al, 2015 ). Exogenous administration of sFlt-1 in pregnant mice have shown to induce placental mitochondrial swelling, oxidative stress and apoptosis in trophoblasts (Jiang et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a potential association between increased soluble anti-angiogenic factors levels and mitochondrial dysfunction has been suggested (Jiang et al, 2015 ). Exogenous administration of sFlt-1 in pregnant mice have shown to induce placental mitochondrial swelling, oxidative stress and apoptosis in trophoblasts (Jiang et al, 2015 ). In addition, preeclamptic plasma mediators induced deleterious effects on mitochondrial function of human umbilical vein endothelial cells (HUVEC) (McCarthy and Kenny, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Soluble Fms-Like Tyrosine Kinase-1 Alters Cellular Metabolism and Mitochondrial Bioenergetics in Preeclampsia

et al. 2018

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Preeclampsia is a maternal hypertensive disorder that affects up to 1 out of 12 pregnancies worldwide. It is characterized by proteinuria, endothelial dysfunction, and elevated levels of the soluble form of the vascular endothelial growth factor receptor-1 (VEGFR-1, known as sFlt-1). sFlt-1 effects are mediated in part by decreasing VEGF signaling. The direct effects of sFlt-1 on cellular metabolism and bioenergetics in preeclampsia, have not been established. The goal of this study was to evaluate whether sFlt-1 causes mitochondrial dysfunction leading to disruption of normal functioning in endothelial and placental cells in preeclampsia. Endothelial cells (ECs) and first-trimester trophoblast (HTR-8/SVneo) were treated with serum from preeclamptic women rich in sFlt-1 or with the recombinant protein. sFlt-1, dose-dependently inhibited ECs respiration and acidification rates indicating a metabolic phenotype switch enhancing glycolytic flux. HTR-8/SVneo displayed a strong basal glycolytic metabolism, remaining less sensitive to sFlt-1-induced mitochondrial impairment. Moreover, results obtained in ECs exposed to serum from preeclamptic subjects demonstrated that increased sFlt-1 leads to metabolic perturbations accountable for mitochondrial dysfunction observed in preeclampsia. sFlt-1 exacerbated mitochondrial reactive oxygen species (ROS) formation and mitochondrial membrane potential dissipation in ECs and trophoblasts exposed to serum from preeclamptic women. Forcing oxidative metabolism by culturing cells in galactose media, further sensitized cells to sFlt-1. This approach let us establish that sFlt-1 targets mitochondrial function in ECs. Effects of sFlt-1 on HTR-8/SVneo cells metabolism were amplified in galactose, demonstrating that sFlt-1 only target cells that rely mainly on oxidative metabolism. Together, our results establish the early metabolic perturbations induced by sFlt-1 and the resulting endothelial and mitochondrial dysfunction in preeclampsia.

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“…reported that in the serum of sFLT-1 treated preeclamptic mice, oxidant malonyl dialdehyde levels were higher and antioxidant superoxide dismutase levels were lower when compared with controls (23). Hence, they suggested that sFLT-1 promoted apoptosis by increasing oxidative stress.…”

Section: Discussionmentioning

confidence: 96%

Decreased oxidative stress may contribute to the disease process in placenta accreta

Öztaş¹,

Özler²,

Ergin³

et al. 2017

Turk J Med Sci

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Background/aim: The main aim of this study was to investigate serum total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), and arylesterase levels in pregnant women with placenta accreta and to compare those with age-matched healthy pregnant women. Materials and methods:A total of 27 pregnant women who had clinically and pathologically proven placenta accreta and 30 age-and BMI-matched healthy pregnant women were enrolled in this case control study. Maternal serum TOS, TAS, OSI, and arylesterase levels were evaluated using logistic regression analysis to determine if there was an association with abnormal placental invasion or not.Results: Decreased OSI (OR= 0.999, 95%CI: 0.998-1.000, P = 0.035) and increased arylesterase levels (OR= 0.981, 95%CI: 0.970-0.993, P = 0.001) were significantly associated with the presence of placenta accreta. Maternal serum TOS, TAS, OSI, and arylesterase levels were not predictive for adverse perinatal outcomes (P > 0.05). Conclusions:Decreased OSI and increased arylesterase levels are significantly associated with placenta accreta and may contribute to the abnormal invasion process.

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A Role of sFlt-1 in Oxidative Stress and Apoptosis in Human and Mouse Pre-Eclamptic Trophoblasts1

Cited by 43 publications

References 33 publications

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

Soluble Fms-Like Tyrosine Kinase-1 Alters Cellular Metabolism and Mitochondrial Bioenergetics in Preeclampsia

Decreased oxidative stress may contribute to the disease process in placenta accreta

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