PUBLICATION
Latrophilin-2 mediates fluid shear stress mechanotransduction at endothelial junctions
- Authors
- 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, M.A.
- ID
- ZDB-PUB-240618-10
- Date
- 2024
- Source
- The EMBO journal 43(15): 3175-3191 (Journal)
- Registered Authors
- Hintzen, Jared, Nicoli, Stefania, Prendergast, Andrew
- Keywords
- Fluid Shear Stress, G Protein-coupled Receptor, Latrophilin, PECAM-1, Vascular Development
- MeSH Terms
-
- Animals
- Endothelial Cells/metabolism
- Human Umbilical Vein Endothelial Cells/metabolism
- Humans
- Intercellular Junctions*/genetics
- Intercellular Junctions*/metabolism
- Mechanotransduction, Cellular*
- Mice
- Receptors, G-Protein-Coupled*/genetics
- Receptors, G-Protein-Coupled*/metabolism
- Receptors, Peptide*/genetics
- Receptors, Peptide*/metabolism
- Stress, Mechanical
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 38886581 Full text @ EMBO J.
Citation
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, M.A. (2024) Latrophilin-2 mediates fluid shear stress mechanotransduction at endothelial junctions. The EMBO journal. 43(15):3175-3191.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping