Compensatory increase of VE-cadherin expression through ETS1 regulates endothelial barrier function in response to TNFα

Colás-Algora, Natalia; García‐Weber, Diego; Cacho-Navas, Cristina; Barroso, Susana; Hernandez-Caballero, Alvaro; Ribas, Catalina; Correas, Isabel; Millán, Jaime

doi:10.1007/s00018-019-03260-9

Cited by 33 publications

(23 citation statements)

References 42 publications

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“…Surprisingly, HIF2α inhibitor had no significant effect on Ve-cadherin mRNA or total cell protein expression (Fig 4e and f) but exclusively abrogated DFO rescue of Ve-cadherin expression on the cell surface (Fig 4g). A similar phenomenon has been recently reported with TNFα and its effect on Ve-cadherin cell surface expression in HUVEC 100 . This supports our hypothesis that TNFα is involved in the mechanisms of our model.…”

Section: Discussionsupporting

confidence: 88%

Endothelial iron homeostasis regulates BBB integrity via the HIF2α – Ve-cadherin pathway

Rand

Ravid

Atrakchi

et al. 2020

Preprint

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The blood-brain barrier serves as the guardian of the CNS, tightly regulating the movement of ions, molecules, and cells between the circulatory system and brain. We have used an in-vitro BBB injury model to gain a better understanding of the mechanisms controlling BBB integrity. This model exposes a co-culture of human stem-cell derived brain-like endothelial cells and brain pericytes that mimic the BBB, to the organophosphate paraoxon. This exposure results in rapid lipid peroxidation, initiating a ferroptosis-like process. Additionally, mitochondrial ROS formation (MRF) and increase in mitochondrial membrane permeability, were also detected leading to apoptotic cell death. Yet, these processes do not directly result in damage to barrier functionality since blocking them does not reverse the increased permeability. We found that the iron chelator, Desferal© significantly decreases MRF and apoptosis subsequent to paraoxon exposure, while also rescuing barrier integrity by inhibiting the liable iron pool increase, inducing HIF2α expression and preventing the degradation of Ve-cadherin on the cell surface. Moreover, the novel nitroxide JP4-039 significantly rescues both injury-induced endothelium cell toxicity and barrier functionality.

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Section: Discussionsupporting

confidence: 88%

Endothelial iron homeostasis regulates BBB integrity via the HIF2α – Ve-cadherin pathway

Rand

Ravid

Atrakchi

et al. 2020

Preprint

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“…To explore the effects of MYPT1-deficient synthetic VSMCs on BBB integrity, the supernatant of human brain microvascular endothelial cells (HBVSMCs) transfected with or without Lv-shMYPT1 was collected and used to stimulate monolayer HBMECs after OGD/R. In addition to TJs, VE-cadherin plays a central role in controlling endothelial barrier function, which is transiently disrupted by proinflammatory cytokines after stroke ( Colás-Algora et al., 2020 ). Immunofluorescence staining for VE-cadherin, ZO-1, and claudin-5 showed that BBB integrity was disrupted when HBMECs were treated with the supernatant of HBVSMCs after OGD/R, which indicated that synthetic VSMCs were deleterious to BBB integrity.…”

Section: Resultsmentioning

confidence: 99%

Synthetic VSMCs induce BBB disruption mediated by MYPT1 in ischemic stroke

et al. 2021

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Summary Vascular smooth muscle cells (VSMCs) have been widely recognized as key players in regulating blood-brain barrier (BBB) function, and their roles are unclear in ischemic stroke. Myosin phosphatase target subunit 1 (MYPT1) is essential for VSMC contraction and maintaining healthy vasculature. We generated VSMC-specific MYPT1 knockout (MYPT1 SMKO ) mice and cultured VSMCs infected with Lv-shMYPT1 to explore phenotypic switching of VSMCs and the accompanied impacts on BBB integrity. We found that MYPT1 deficiency induced phenotypic switching of synthetic VSMCs, which aggravated BBB disruption. Proteomic analysis identified evolutionarily conserved signaling intermediates in Toll pathways (ECSIT) as a downstream molecule that promotes activation of synthetic VSMCs and contributed to IL-6 expression. Knocking down ECSIT rescued phenotypic switching of VSMCs and BBB disruption. Additionally, inhibition of IL-6 decreased BBB permeability. These findings reveal that MYPT1 deficiency activated phenotypic switching of synthetic VSMCs and induced BBB disruption through ECSIT-IL-6 signaling after ischemic stroke.

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“…Regulation of ETS1 expression in brain ECs is still unknown. To uncover the signal pathway mediating ETS1 upregulation, we analyzed the expression of Ets1 in bEND.3 cells upon stimulation of VEGFA, TNFα and TGFβ2, which can increase ETS1/Ets1 expression in human umbilical vein endothelial cells (HUVECs) or renal cells (39)(40)(41). Neither TNFα nor VEGFA could increase ETS1 expression in bEND.3 cells (Figure 2A).…”

Section: Tgfβ Increases Ets1 Expression In Brain Ecsmentioning

confidence: 99%

Uncovering a Key Role of ETS1 on Vascular Abnormality in Glioblastoma

Tang¹,

Li²,

Liu³

et al. 2021

Pathol. Oncol. Res.

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Glioblastoma (GBM) is the most aggressive type of brain tumor. Microvascular proliferation and abnormal vasculature are the hallmarks of the GBM, aggravating disease progression and increasing patient morbidity. Here, we uncovered a key role of ETS1 on vascular abnormality in glioblastoma. ETS1 was upregulated in endothelial cells from human tumors compared to endothelial cells from paired control brain tissue. Knockdown of Ets1 in mouse brain endothelial cells inhibited cell migration and proliferation, and suppressed expression of genes associated with vascular abnormality in GBM. ETS1 upregulation in tumor ECs was dependent on TGFβ signaling, and targeting TGFβ signaling by inhibitor decreased tumor angiogenesis and vascular abnormality in CT-2A glioma model. Our results identified ETS1 as a key factor regulating tumor angiogenesis, and suggested that TGFβ inhibition may suppress the vascular abnormality driven by ETS1.

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Compensatory increase of VE-cadherin expression through ETS1 regulates endothelial barrier function in response to TNFα

Cited by 33 publications

References 42 publications

Endothelial iron homeostasis regulates BBB integrity via the HIF2α – Ve-cadherin pathway

Endothelial iron homeostasis regulates BBB integrity via the HIF2α – Ve-cadherin pathway

Synthetic VSMCs induce BBB disruption mediated by MYPT1 in ischemic stroke

Uncovering a Key Role of ETS1 on Vascular Abnormality in Glioblastoma

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