Latrophilin-2 mediates fluid shear stress mechanotransduction at endothelial junctions.

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  • Additional Information
    • Source:
      Publisher: Wiley Blackwell Country of Publication: England NLM ID: 8208664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2075 (Electronic) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE
    • Publication Information:
      Publication: 2014- : London : Wiley Blackwell
      Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-
    • Subject Terms:
      Intercellular Junctions*/metabolism ; Intercellular Junctions*/genetics ; Mechanotransduction, Cellular* ; Receptors, G-Protein-Coupled*/metabolism ; Receptors, G-Protein-Coupled*/genetics ; Receptors, Peptide*/metabolism ; Receptors, Peptide*/genetics; Animals ; Humans ; Mice ; Endothelial Cells/metabolism ; Human Umbilical Vein Endothelial Cells/metabolism ; Stress, Mechanical ; Zebrafish/metabolism ; Zebrafish/genetics
    • Abstract:
      Endothelial cell responses to fluid shear stress from blood flow are crucial for vascular development, function, and disease. A complex of PECAM-1, VE-cadherin, VEGF receptors (VEGFRs), and Plexin D1 located at cell-cell junctions mediates many of these events. However, available evidence suggests that another mechanosensor upstream of PECAM-1 initiates signaling. Hypothesizing that GPCR and Gα proteins may serve this role, we performed siRNA screening of Gα subunits and found that Gαi2 and Gαq/11 are required for activation of the junctional complex. We then developed a new activation assay, which showed that these G proteins are activated by flow. We next mapped the Gα residues required for activation and developed an affinity purification method that used this information to identify latrophilin-2 (Lphn2/ADGRL2) as the upstream GPCR. Latrophilin-2 is required for all PECAM-1 downstream events tested. In both mice and zebrafish, latrophilin-2 is required for flow-dependent angiogenesis and artery remodeling. Furthermore, endothelial-specific knockout demonstrates that latrophilin plays a role in flow-dependent artery remodeling. Human genetic data reveal a correlation between the latrophilin-2-encoding Adgrl2 gene and cardiovascular disease. Together, these results define a pathway that connects latrophilin-dependent G protein activation to subsequent endothelial signaling, vascular physiology, and disease.
      (© 2024. The Author(s).)
    • Comments:
      Update of: bioRxiv. 2024 Jun 14:2024.06.13.598386. doi: 10.1101/2024.06.13.598386. (PMID: 38915515)
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    • Grant Information:
      R01 HL130246 United States HL NHLBI NIH HHS; R01 HL171054 United States HL NHLBI NIH HHS; R01 DK134329 United States DK NIDDK NIH HHS; 805 MEXT | Japan Society for the Promotion of Science (JSPS); 5R01HL130246-05 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); RO1 HL75092,RO1 HL151469 Foundation for the National Institutes of Health (FNIH); R01 HL075092 United States HL NHLBI NIH HHS
    • Contributed Indexing:
      Keywords: Fluid Shear Stress; G Protein-coupled Receptor; Latrophilin; PECAM-1; Vascular Development
    • Accession Number:
      0 (Receptors, G-Protein-Coupled)
      0 (Receptors, Peptide)
      0 (ADGRL2 protein, human)
    • Publication Date:
      Date Created: 20240617 Date Completed: 20240801 Latest Revision: 20240925
    • Publication Date:
      20240925
    • Accession Number:
      PMC11294477
    • Accession Number:
      10.1038/s44318-024-00142-0
    • Accession Number:
      38886581