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

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Abstract

VE-cadherin plays a central role in controlling endothelial barrier function, which is transiently disrupted by proinflammatory cytokines such as tumor necrosis factor (TNFα). Here we show that human endothelial cells compensate VE-cadherin degradation in response to TNFα by inducing VE-cadherin de novo synthesis. This compensation increases adherens junction turnover but maintains surface VE-cadherin levels constant. NF-κB inhibition strongly reduced VE-cadherin expression and provoked endothelial barrier collapse. Bacterial lipopolysaccharide and TNFα upregulated the transcription factor ETS1, in vivo and in vitro, in an NF-κB dependent manner. ETS1 gene silencing specifically reduced VE-cadherin protein expression in response to TNFα and exacerbated TNFα-induced barrier disruption. We propose that TNFα induces not only the expression of genes involved in increasing permeability to small molecules and immune cells, but also a homeostatic transcriptional program in which NF-κB- and ETS1-regulated VE-cadherin expression prevents the irreversible damage of endothelial barriers.

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Acknowledgements

The expert technical advice of the Confocal Microscopy Facility and the Genomic Facility are gratefully acknowledged. The work was supported by Grants SAF2017-88187-R and S2017/BMD-3817 TomoXliver (to J.M.), BFU2015–67266-R (to I.C) and Instituto de Salud Carlos III (PI18/01662 to CR, co-funded with European FEDER contribution) and of the Programa de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE. S.B.F is supported by Endocornea2, convenio colaboración CSIC, funded by Instituto de Investigación Fundación Jiménez Díaz. An institutional support of Fundación Ramón Areces to the CBMSO is also acknowledged. DGW and CCN are recipients of FPI fellowships from MINECO. NCA and AC are recipients of FPU fellowships from MECD. We also thank Dr. Phil Mason, who provided English language support, and Dr. Miguel A. Alonso, for helpful comments.

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Author notes

  1. Diego García-Weber

    Present address: INSERM, U1016, Institut Cochin, Paris, France

  2. Natalia Colás-Algora and Diego García-Weber contributed equally to this work.

Authors and Affiliations

  1. Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), 28049, Madrid, Spain

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

  2. Departamento de Biología Molecular, Universidad Autónoma de Madrid, 28049, Madrid, Spain

    Alvaro Caballero, Catalina Ribas & Isabel Correas

  3. Instituto de Investigación Sanitaria La Princesa, 28006, Madrid, Spain

    Alvaro Caballero & Catalina Ribas

  4. CIBER de Enfermedades Cardiovasculares, ISCIII (CIBERCV), 28029, Madrid, Spain

    Catalina Ribas

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  1. Natalia Colás-Algora
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Contributions

DGW, NCA and JM contributed to the conception and experimental design. DGW, NCA, CCN and SBF performed the experiments and acquired the data. AC and CR help carry out in vivo experiments and isolated lung endothelial cells. DGW and NCA analyzed the data, IC and CR provided material support, and reviewed the manuscript, which was written by JM.

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Correspondence to Diego García-Weber or Jaime Millán.

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Colás-Algora, N., García-Weber, D., Cacho-Navas, C. et al. Compensatory increase of VE-cadherin expression through ETS1 regulates endothelial barrier function in response to TNFα. Cell. Mol. Life Sci. 77, 2125–2140 (2020). https://doi.org/10.1007/s00018-019-03260-9

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