Endothelial dysfunction in pregnancy metabolic disorders

Echeverría, César; Eltit, Felipe; Santibanez, Juan F; Gatica, Sebastián; Cabello-Verrugio, Claudio; Simón, Felipe

doi:10.1016/j.bbadis.2019.02.009

Cited by 45 publications

(37 citation statements)

References 158 publications

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“…It is postulated that in severe PE, ET-1 production is increased to the extent that it loses its paracrine directionality and leads to increased circulating levels and, together with AT1-AA, induces the local and systemic release of oxidant substances [32][33][34]. Interestingly, the administration of ascorbic acid increases the flow-mediated vasodilation in large arteries of women who have formerly exhibited PE, further demonstrating the role of oxidative stress in maintaining vascular function in PE [35]. Supporting these data, we were able to show that the presence of quercetin during the exposure of placental explants to hypoxia concentration-dependently protected the vascular contraction induced by placental HCM.…”

Section: Discussionmentioning

confidence: 98%

Placental hypoxia-induced alterations in vascular function, morphology, and endothelial barrier integrity

et al. 2020

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Preeclampsia (PE) is a pregnancy-related disorder characterized by hypertension and proteinuria that affects 3-10% of all pregnancies. Although its pathophysiology remains obscure, placental hypoxia-induced oxidative stress and alterations in vascular function, morphology, and endothelial barrier integrity are considered to play a key role in the development of preeclampsia. In this study, placental villous explants of noncomplicated placentae and BeWo cells were subjected to hypoxia. The effect of placental hypoxic-conditioned medium (HCM) on intraluminal-induced contraction and endothelial barrier integrity in chorionic arteries was investigated using pressure myography. The impact of BeWo cell HCM on endothelial cell viability, reactive oxygen species formation and inflammation was also determined. Alterations in arterial morphology and contractile responsiveness to the thromboxane A2 analog (U46619) after exposure to placental HCM were examined immunohistochemically and by wire myography, respectively. Intraluminal administration of placental HCM induced vasoconstriction and increased the endothelial permeability for KCl, which was concentration-dependently prevented by quercetin. Placental and BeWo cell HCMs decreased endothelial cell viability, increased the production of reactive oxygen species and enhanced the secretion of IL-6 and IL-8. The cross-sectional area of the arterial media was increased upon exposure to placental HCM, which was associated with increased vascular proliferation and contractile responsiveness to U46619, and all of these effects were prevented by the antioxidants quercetin and RRR-α-tocopherol. This study is the first to comprehensively demonstrate the link between factors secreted by placental cells in response to hypoxia and vascular abnormalities and paves the way for new diagnostic approaches and therapies to better protect the maternal vasculature during and after a preeclampsia-complicated pregnancy.

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Section: Discussionmentioning

confidence: 98%

Placental hypoxia-induced alterations in vascular function, morphology, and endothelial barrier integrity

et al. 2020

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“…It has been previously postulated that endothelial dysfunction plays a pivotal role in the detrimental health outcomes recorded in PE and GDM, playing a particular role in hypertension, proteinuria, cardiovascular risk, obesity and hyperlipidemia (27). Recent studies have shown that women diagnosed with PE and GDM have a significantly lower flow-mediated dilation (FMD) compared with their healthy counterparts, suggestive of increased endothelial damage in these patients (1,28).…”

Section: Does Pe and Gdm-mediated Endothelial Dysfunction Contribute mentioning

confidence: 99%

Mechanisms of Endothelial Dysfunction in Pre-eclampsia and Gestational Diabetes Mellitus: Windows Into Future Cardiometabolic Health?

et al. 2020

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Placental insufficiency and adipose tissue dysregulation are postulated to play key roles in the pathophysiology of both pre-eclampsia (PE) and gestational diabetes mellitus (GDM). A dysfunctional release of deleterious signaling motifs can offset an increase in circulating oxidative stressors, pro-inflammatory factors and various cytokines. It has been previously postulated that endothelial dysfunction, instigated by signaling from endocrine organs such as the placenta and adipose tissue, may be a key mediator of the vasculopathy that is evident in both adverse obstetric complications. These signaling pathways also have significant effects on long term maternal cardiometabolic health outcomes, specifically cardiovascular disease, hypertension, and type II diabetes. Recent studies have noted that both PE and GDM are strongly associated with lower maternal flow-mediated dilation, however the exact pathways which link endothelial dysfunction to clinical outcomes in these complications remains in question. The current diagnostic regimen for both PE and GDM lacks specificity and consistency in relation to clinical guidelines. Furthermore, current therapeutic options rely largely on clinical symptom control such as antihypertensives and insulin therapy, rather than that of early intervention or prophylaxis. A better understanding of the pathogenic origin of these obstetric complications will allow for more targeted therapeutic interventions. In this review we will explore the complex signaling relationship between the placenta and adipose tissue in PE and GDM and investigate how these intricate pathways affect maternal endothelial function and, hence, play a role in acute pathophysiology and the development of future chronic maternal health outcomes.

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“…A great number of reports have revealed that the microvascular cell and vascular endothelial cell (VECs) dysfunctions occurred in the umbilical cord and placenta in GDM might lead to immediate or long-term cardiovascular disease risk ( Di Fulvio et al., 2014 ; Sultan et al., 2015 ; Zhou et al., 2016 ; Amrithraj et al., 2017 ). And endothelial dysfunction is a key cause of pathogenesis when pregnancy metabolic disorders occur, including GDM, hypertensive disorders, obesity, and hyperlipidemia ( Echeverria et al., 2020 ). Further, endothelial dysfunction could occur before pregnancy and predisposes women to hypertension in pregnancy and pre-eclampsia, and the latter could induce long-term changes in endothelial function, which could have implications for development of cardiovascular disease in later life ( Karthikeyan and Lip, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction via Downregulation of p65 and Upregulation of Nrf2

et al. 2020

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Gestational diabetes mellitus (GDM) causes oxidative stress in mothers and infants and causes vascular endothelial dysfunction, which is a key factor for maternal and fetal cardiovascular diseases in the later stage of GDM, seriously threatening the life and health of mothers and infants. Nowadays, metformin (MET) has been discovered to improve endothelial function, but studies regarding the mechanism of MET improving endothelial cell function and alleviating endothelial function under hyperglycemia are still extremely limited. We aimed to investigate whether MET exerts its protective role against hyperglycemia-induced endothelial dysfunction through p65 and Nrf2. In our studies, applying cell migration assay and tube formation assay, we observed an obvious improvement of endothelial function under MET-treated, as characterized by that MET accelerated GDM-attenuated migration and angiogenesis of HUVECs. And ELISA assay results uncovered that Nrf2 expression level was decreased in GDM placenta, HVUECs and maternal serum comparing with normal group, however activation Nrf2 largely ameliorated tube formation under hyperglycemic condition. Furthermore, MET elevated the Nrf2 expression level and the level of nuclear Nrf2 accumulation in hyperglycemic HUVECs. Besides, preliminary evidence predicted that Nrf2 expression was modulated by transcription factor p65, which was increased in GDM peripheral blood, placenta and HUVECs, and suppression of p65 could recover GDM-induced suppression of angiogenesis. In addition, we also confirmed MET restores the GDM-induced angiogenesis impairment may via downregulation of p65 and upregulation of Nrf2. Taken together, the endothelial protective effect of MET under GDM (HG) conditions could be partly attributed to its role in downregulating p65 and upregulating Nrf2.

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Endothelial dysfunction in pregnancy metabolic disorders

Cited by 45 publications

References 158 publications

Placental hypoxia-induced alterations in vascular function, morphology, and endothelial barrier integrity

Placental hypoxia-induced alterations in vascular function, morphology, and endothelial barrier integrity

Mechanisms of Endothelial Dysfunction in Pre-eclampsia and Gestational Diabetes Mellitus: Windows Into Future Cardiometabolic Health?

Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction via Downregulation of p65 and Upregulation of Nrf2

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