{Reference Type}: Journal Article
{Title}: Latrophilin-2 mediates fluid shear stress mechanotransduction at endothelial junctions.
{Author}: Tanaka K;Chen M;Prendergast A;Zhuang Z;Nasiri A;Joshi D;Hintzen J;Chung M;Kumar A;Mani A;Koleske A;Crawford J;Nicoli S;Schwartz MA;
{Journal}: EMBO J
{Volume}: 43
{Issue}: 15
{Year}: 2024 Aug 17
{Factor}: 14.012
{DOI}: 10.1038/s44318-024-00142-0
{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.