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

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. Synopsis: Fluid shear stress from blood flow induces vascular endothelium remodeling by triggering signaling events through the PECAM-1/VE-cadherin/VEGF receptor/Plexin D1 complex at cell-cell junctions. This study shows that the adhesion G protein-coupled receptor latrophilin-2 (Lphn2) activates Gαi2 and Gαq/11 to induce shear stress-dependent activation of this pathway. Shear stress-induced activation of Gαi2 and Gαq/11 is required for endothelial cell alignment and activation of junctional signaling events. Lphn2 is the upstream GPCR that co-localizes and interacts with PECAM-1 to activate its signaling. Deletion of Lphn2 from zebrafish and mice blocks multiple flow-dependent developmental and adult vascular remodeling processes. Shear stress-induced activation of Gαi2 and Gαq/11 by the adhesion receptor latrophilin-2 is required for PECAM-1 signaling and vascular remodeling in zebrafish and mice. [ABSTRACT FROM AUTHOR]