Endothelial FOXO1 Lactylation: A New Link Between Disturbed Flow and Atherosclerosis

Endothelial cells (ECs) line the inner layer of the blood vessels and are subjected to hemodynamic shear stress, the frictional force derived from blood flow, most prominently in arteries 1,2 .Vascular structure influences the intensity and patterns of hemodynamic shear stress.Blood flow through straight, non-branching arteries generates unidirectional laminar shear.Conversely, curved or branching arteries can produce disturbed flow, resulting in oscillatory shear stress.Atherosclerotic plaques preferentially develop in curved and branching regions of the arteries with disturbed blood flow 1,2 .ECs detect the patterns and magnitudes of shear stress through mechanoreceptors 3 .Oscillatory shear stress causes these receptors to drive pro-inflammatory responses 3 .As part of these responses, ECs recruit circulating leukocytes that extravasate into the subendothelial space.These ECs also change their endocytic and metabolic behavior 1,2 .Disturbed flow causes ECs to increase transcytosis of circulating LDL, thus driving foam cell formation and atherosclerosis development.While ECs exposed to laminar flow use oxidative phosphorylation, disturbed flow increases use of glycolysis at the expense of oxidative phosphorylation 1,2 .The switch to glycolysis contributes to vascular inflammation and atherosclerosis progression 1 .Omics studies have demonstrated that laminar and oscillatory shear stress differentially regulate endothelial transcriptomic and epigenomic landscapes, modulating key EC functions 1,4 .Defining the mechanisms by which laminar flow inhibits and disturbed flow promotes inflammatory responses in atherosclerosis will be pivotal for understanding roles of endothelial cells in the pathogenesis of atherosclerosis and for developing new therapeutic approaches.FOXO1 belongs to the FOXO family of transcription factors.FOXOs coordinate responses to environmental changes 5 .They play key roles in many cellular processes, including cellular metabolism, apoptosis, autophagy, cell cycle arrest, inflammation, and immune response 5,6 .The FOXO protein structure consists of an N-terminal DNA binding domain (DBD), a nuclear localization signal motif (NLS), a nuclear export sequence motif (NES), and a C-terminal transcription activation domain (TAD).The NLS and NES control nuclear