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A non-canonical Notch complex regulates adherens junctions and vascular barrier function

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Abstract

The vascular barrier that separates blood from tissues is actively regulated by the endothelium and is essential for transport, inflammation, and haemostasis1. Haemodynamic shear stress plays a critical role in maintaining endothelial barrier function2, but how this occurs remains unknown. Here, using an engineered organotypic model of perfused microvessels and confirming in mouse models, we identify that activation of the Notch1 transmembrane receptor directly regulates vascular barrier function through a non-canonical, transcription independent signalling mechanism that drives adherens junction assembly. Shear stress triggers Dll4-dependent proteolytic activation of Notch1 to reveal the Notch1 transmembrane domain—the key domain that mediates barrier establishment. Expression of the Notch1 transmembrane domain is sufficient to rescue Notch1 knockout-induced defects in barrier function, and does so by catalysing the formation of a novel receptor complex in the plasma membrane consisting of VE-cadherin, the transmembrane protein tyrosine phosphatase LAR, and the Rac1 GEF Trio. This complex activates Rac1 to drive adherens junction assembly and establish barrier function. Canonical Notch transcriptional signalling is highly conserved throughout metazoans and is required for many processes in vascular development, including arterial-venous differentiation3, angiogenesis4, and remodelling5; here, we establish the existence of a previously unappreciated non-canonical cortical signalling pathway for Notch1 that regulates vascular barrier function, and thus provide a mechanism by which a single receptor might link transcriptional programs with adhesive and cytoskeletal remodelling.

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Author information

Author notes

    • William J. Polacheck
    •  & Matthew L. Kutys

    Equal contributions

Affiliations

  1. The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA

    • William J. Polacheck
    • , Matthew L. Kutys
    • , Jinling Yang
    • , Jeroen Eyckmans
    •  & Christopher S. Chen
  2. The Biological Design Center and Department of Biomedical Engineering, Boston University, Boston, MA

    • William J. Polacheck
    • , Matthew L. Kutys
    • , Jinling Yang
    • , Jeroen Eyckmans
    •  & Christopher S. Chen
  3. Yale Cardiovascular Research Center, Departments of Internal Medicine, Genetics, and Biomedical Engineering, New Haven, CT

    • Yinyu Wu
    • , Hema Vasavada
    •  & Karen K. Hirschi

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Corresponding author

Correspondence to Christopher S. Chen.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Tables 1–2 and the uncropped western blot scans with size marker indications.

  2. 2.

    Life Sciences Reporting Summary