TNF-alpha inhibits pregnancy-adapted Ca2+ signaling in uterine artery endothelial cells

Ampey, Amanda C.; Boeldt, Derek S.; Clemente, Luca; Grummer, Mary A.; Feng, Yi; Magness, Ronald R.; Bird, Ian M.

doi:10.1016/j.mce.2019.02.008

Cited by 14 publications

(13 citation statements)

References 57 publications

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“…It should be noted, however, that most functional studies utilize concentrations far greater than 1 ng/mL and typically seek to tie endothelial dysfunction to oxidative stress (Ampey et al 2019). Our data suggesting a beneficial effect at 1 ng/mL is relevant since normal healthy pregnancies are a state of mild inflammation and yet TNFα concentrations in normal pregnancy rarely reach 1 ng/mL (Xie et al 2011, Lau et al 2013, although it may be approached in the circulation in PE subjects and exceeded at the uteroplacental interface.…”

Section: Journal Of Endocrinologymentioning

confidence: 73%

“…a single dose potentiated ATP-stimulated Ca 2+ response. This was surprising since we have previously shown that in HUVECs and UAECs that TNFα reduces individual Ca 2+ bursts (Ampey et al 2019, Mauro et al 2020. Indeed, the vast majority of studies report a link between TNFα and endothelial dysfunction or immune responses.…”

Section: Journal Of Endocrinologymentioning

confidence: 89%

“…Curiously, this centers around the VEGF 165 alone peak, but not the TNFα alone peak. Because both VEGF 165 and TNFα are known to phosphorylate Cx43 at Src-kinase-sensitive residues (Solan & Lampe 2014, Boeldt et al 2015, Ampey et al 2019, Mauro et al 2020, perhaps 1 ng/mL of each begins to overstimulate Src signaling pathways and precipitates inhibitory Cx43 phosphorylation. Further studies would be necessary to fully elucidate the positive/ negative switch.…”

Section: Journal Of Endocrinologymentioning

confidence: 99%

“…In pregnancy, there are changes in levels of many growth factors and cytokines as compared to the non-pregnant state, and further changes occur in PE compared to normal pregnancies. Stimulation of kinase signaling cascades and transcriptional regulation as a consequence of changing growth factor and cytokine concentrations is, therefore, a prime candidate for promoting endothelial dysfunction, likely through interfering with these cell-cell connections that are so critical to pregnancy-adapted endothelial function (Boeldt et al 2015, Ampey et al 2019, Mauro et al 2020.…”

Section: Introductionmentioning

confidence: 99%

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Cytokine concentrations direct endothelial function in pregnancy and preeclampsia

Mauro

Khurshid

Berdahl

et al. 2021

Journal of Endocrinology

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Endothelial dysfunction is a prominent feature of preeclampsia, a hypertensive disorder of pregnancy, and contributes to multiple symptoms characteristic of the syndrome. A myriad of growth factors and cytokines are dysregulated in preeclampsia as compared to normal pregnancy, however a complete appreciation of the effect of changing concentrations of these factors on endothelial function is lacking. In this study we evaluate the effect of a variety of growth factors and cytokines on Ca2+ signaling and monolayer integrity. We report that VEGF165, TNFα,EGF, and IL-1β either improve or inhibit Ca2+ signaling depending on dose, whereas TNFα and IL-1β reduce monolayer integrity and bFGF increases monolayer integrity. Additionally, to model the effects of combinations of growth factors and cytokines, we screened for Ca2+ signaling changes in response to 16 dose combinations of VEGF165 and TNFα together. This revealed an optimal combination capable of supporting pregnancy-adapted Ca2+ signaling, and that changes in either VEGF165 or TNFα dose would result in a shift towards suppressed function. This study shows in detail how growth factor or cytokine concentration effects endothelial cell function. Such data can be used to model how changing growth factor and cytokine levels in normal pregnancy may contribute to healthy endothelial function and in preeclampsia may promote endothelial dysfunction. The results of VEGF165 and TNFα combination treatments suggest that more complex growth factor and cytokine combination modeling may be important in order to more accurately understand the effects of circulating factors on the endothelial function.

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Section: Journal Of Endocrinologymentioning

confidence: 73%

Section: Journal Of Endocrinologymentioning

confidence: 89%

Section: Journal Of Endocrinologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cytokine concentrations direct endothelial function in pregnancy and preeclampsia

Mauro

Khurshid

Berdahl

et al. 2021

Journal of Endocrinology

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“…TNFα promotes mitochondrial ROS production and eNOS downregulation in HUVECs [295][296][297]. Pregnancy enhances sustained Ca 2+ bursts and eNOS activity in ovine uterine artery endothelial cells by promoting connexin 43 function, which is suppressed by TNFα [298,299]. Further evidence supporting the involvement of TNFα in uterine vascular dysfunction in preeclampsia comes from animal studies.…”

Section: Inflammationmentioning

confidence: 98%

Uteroplacental Circulation in Normal Pregnancy and Preeclampsia: Functional Adaptation and Maladaptation

Zhang

2021

IJMS

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Uteroplacental blood flow increases as pregnancy advances. Adequate supply of nutrients and oxygen carried by uteroplacental blood flow is essential for the well-being of the mother and growth/development of the fetus. The uteroplacental hemodynamic change is accomplished primarily through uterine vascular adaptation, involving hormonal regulation of myogenic tone, vasoreactivity, release of vasoactive factors and others, in addition to the remodeling of spiral arteries. In preeclampsia, hormonal and angiogenic imbalance, proinflammatory cytokines and autoantibodies cause dysfunction of both endothelium and vascular smooth muscle cells of the uteroplacental vasculature. Consequently, the vascular dysfunction leads to increased vascular resistance and reduced blood flow in the uteroplacental circulation. In this article, the (mal)adaptation of uteroplacental vascular function in normal pregnancy and preeclampsia and underlying mechanisms are reviewed.

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Mononuclear Cells Negatively Regulate Endothelial Ca2+ Signaling

et al. 2023

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TNF-alpha inhibits pregnancy-adapted Ca2+ signaling in uterine artery endothelial cells

Cited by 14 publications

References 57 publications

Cytokine concentrations direct endothelial function in pregnancy and preeclampsia

Cytokine concentrations direct endothelial function in pregnancy and preeclampsia

Uteroplacental Circulation in Normal Pregnancy and Preeclampsia: Functional Adaptation and Maladaptation

Mononuclear Cells Negatively Regulate Endothelial Ca2+ Signaling

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