Differential control of uterine artery endothelial monolayer integrity by TNF and VEGF is achieved through multiple mechanisms operating inside and outside the cell – Relevance to preeclampsia

Ampey, Amanda C.; Dahn, Rachel L.; Grummer, Mary A.; Bird, Ian M.

doi:10.1016/j.mce.2021.111368

Cited by 5 publications

(6 citation statements)

References 15 publications

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“…Interestingly, these molecular pathways are reported in the placentas of PE patients [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. In addition, we found that TNF-α, MMP7, ADAMts5 mRNA levels were increased in the PE-like model, which is consistent with prior studies of human PE placentas where they are implicated to be involved in PE pathogenesis [ 15 , 16 , 17 , 18 ]. These results indicate that placental 11β-HSD2 is a key factor in PE development, and the 11β-HSD2 dysfunction-induced PE-like rat model resembles the characteristics of PE in humans.…”

Section: Discussionsupporting

confidence: 91%

“…Of note, many genes including TNF-α, MMP7, ADAMts5, Igf1 etc. ( Figure 1 A, orange marked) have been reported to be associated with PE development [ 15 , 16 , 17 , 18 ]. KEGG pathway GO enrichment analysis showed that amino acid metabolism, sphingolipid pathway, mitochondrial functionalities, oxidative phosphorylation (OXPHOS), carbon metabolism and glutathione metabolism were affected in a PE-like model ( Supplemental Figure S3B,C , Figure 1 C).…”

Section: Resultsmentioning

confidence: 99%

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Mitochondria Targeted Antioxidant Significantly Alleviates Preeclampsia Caused by 11β-HSD2 Dysfunction via OPA1 and MtDNA Maintenance

Long

Huang²,

Tang

et al. 2022

Antioxidants

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We have previously demonstrated that placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) dysfunction contributes to PE pathogenesis. We sought to elucidate molecular mechanisms underlying 11β-HSD2 dysfunction-induced PE and to seek potential therapeutic targets using a 11β-HSD2 dysfunction-induced PE-like rat model as well as cultured extravillous trophoblasts (EVTs) since PE begins with impaired function of EVTs. In 11β-HSD2 dysfunction-induced PE-like rat model, we revealed that placental mitochondrial dysfunction occurred, which was associated with mitDNA instability and impaired mitochondrial dynamics, such as decreased optic atrophy 1 (OPA1) expression. MitoTEMPO treatment significantly alleviated the hallmark of PE-like features and improved mitDNA stability and mitochondrial dynamics in the placentas of rat PE-like model. In cultured human EVTs, we found that 11β-HSD2 dysfunction led to mitochondrial dysfunction and disrupted mtDNA stability. MitoTEMPO treatment improved impaired invasion and migration induced by 11β-HSD2 dysfunction in cultured EVTs. Further, we revealed that OPA1 was one of the key factors that mediated 11β-HSD2 dysfunction-induced excess ROS production, mitochondrial dysfunction and mtDNA reduction. Our data indicates that 11β-HSD2 dysfunction causes mitochondrial dysfunctions, which impairs trophoblast function and subsequently results in PE development. Our study immediately highlights that excess ROS is a potential therapeutic target for PE.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Mitochondria Targeted Antioxidant Significantly Alleviates Preeclampsia Caused by 11β-HSD2 Dysfunction via OPA1 and MtDNA Maintenance

Long

Huang²,

Tang

et al. 2022

Antioxidants

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“…However, a meta-analysis indicated that there was no evidence of a difference in the circulating levels of IL-17 between patients with PE and controls . Additionally, several studies have demonstrated that TNF may be associated with PE and TNF-α may be a potential biomarker for PE. ,, More studies are required to explore the roles of the IL-17 and TNF signaling pathways in the development of PE. Additionally, other pathways, including MAPK and toll-like receptor signaling pathways, were significant after changing the background to 92 inflammation-related proteins.…”

Section: Discussionmentioning

confidence: 99%

Plasma Olink Proteomics Identifies CCL20 as a Novel Predictive and Diagnostic Inflammatory Marker for Preeclampsia

Wang

Yip

et al. 2022

J. Proteome Res.

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Inflammation is generally thought to be involved in the occurrence and development of preeclampsia (PE), but its specific effect on PE remains unclear. In the present study, the expression levels of 92 inflammation-related proteins were measured in the late pregnancy maternal plasma from patients with PE (n = 15) and normal pregnant controls (n = 15) using the Olink inflammation panel based on the highly sensitive and specific proximity extension assay technology. A total of 28 inflammation-related markers differed between the PE and control groups. Among them, fibroblast growth factor 21 (FGF-21) and cysteine–cysteine motif chemokine ligand 20 (CCL20) had the largest fold changes. We further validated the levels of CCL20 in the late (43 with PE and 44 controls) and early (37 with PE and 37 controls) pregnancy maternal plasma using enzyme-linked immunosorbent assay (ELISA). To the best of our knowledge, for the first time, CCL20 was found to be upregulated in the late and early pregnancy plasma of patients with PE and had an area under the curve (AUC) of 0.753 and 0.668, respectively. In conclusion, patients with PE had increased levels of most inflammatory markers, and CCL20 might be a novel potential predictive and diagnostic biomarker for PE.

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“…Increased permeability in HUVEC MPS upon treatment with inflammatory mixture is in line with previous studies on lymphatic vessel MPS with IL-6 treatment 38 and HUVECs on 2D cultures treated with TNFα. 16 It is plausible that TNFα is majorly responsible for the poor barrier function 16 and likely works via decreased membrane localization of ZO-1 and VE-cadherin proteins as alluded to in uterine artery endothelial cells 39 and in corneal endothelial cells. 40 Barrier function was improved in HUVEC MPS containing embedded PBMCs, perhaps due to slow and sustained release of relatively low-concentration cytokines that could offer some beneficial effects to the monolayer.…”

Section: Discussionmentioning

confidence: 99%

Immune cells and inflammatory mediators cause endothelial dysfunction in a vascular microphysiological system

Rengarajan,

Goldblatt,

Beebe

et al. 2024

Lab Chip

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Differential control of uterine artery endothelial monolayer integrity by TNF and VEGF is achieved through multiple mechanisms operating inside and outside the cell – Relevance to preeclampsia

Cited by 5 publications

References 15 publications

Mitochondria Targeted Antioxidant Significantly Alleviates Preeclampsia Caused by 11β-HSD2 Dysfunction via OPA1 and MtDNA Maintenance

Mitochondria Targeted Antioxidant Significantly Alleviates Preeclampsia Caused by 11β-HSD2 Dysfunction via OPA1 and MtDNA Maintenance

Plasma Olink Proteomics Identifies CCL20 as a Novel Predictive and Diagnostic Inflammatory Marker for Preeclampsia

Immune cells and inflammatory mediators cause endothelial dysfunction in a vascular microphysiological system

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