To cope with mechanical stress, junctional proteins called cadherins can sense and transduce extracellular forces into signalling cascades that regulate cell metabolism and trigger adaptive responses, including AMP-activated protein kinase (AMPK) activation and fortification of the actin cytoskeleton and cell junctions. Vascular endothelial cells experience fluid shear stress generated by blood flow, which causes cells to align parallel to the direction of flow. How vascular endothelial cadherin (VE-cadherin) activates AMPK and the downstream effects of mechanotransduction in endothelial cells are still unclear. In this study (Cronin et al., 2024), Kris DeMali and colleagues explore VE-cadherin-mediated signal transduction in response to shear stress in endothelial cell cultures. They find that VE-cadherin recruits liver kinase B1 (LKB1) to phosphorylate AMPK, subsequently triggering enrichment of endothelial nitric oxide synthase (eNOS) at adherens junctions. Nitric oxide generated by eNOS activation promotes vasodilation. Furthermore, they show that actin cytoskeleton remodelling, adherens junction reinforcement and cell alignment are dependent on VE-cadherin-mediated AMPK activation. These effects are accompanied by a >3-fold increase in glucose uptake, suggesting that VE-cadherin controls an endothelial mechanotransduction programme that links cytoskeletal mechanics, cell metabolism and vasodilation to coordinate physiological responses of the vascular endothelium to shear stress.
