Lactate induces vascular permeability via disruption of VE-cadherin in endothelial cells during sepsis
Year: 2022
Type: article
Abstract: Circulating lactate levels are a critical biomarker for sepsis and are positively correlated with sepsis-associated mortality. We investigated whether lactate plays a biological role in causing endothelial barrier dysfunction in sepsis. We showed that lactate causes vascular permeability and worsens organ dysfunction in CLP sepsis. Mechanistically, lactate induces ERK-dependent activation of calpain1/2 for VE-cadherin proteolytic cleavage, leading to the enhanced endocytosis of VE-cadherin in endothelial cells. In addition, we found that ERK2 interacts with VE-cadherin and stabilizes VE-cadherin complex in resting endothelial cells. Lactate-induced ERK2 phosphorylation promotes ERK2 disassociation from VE-cadherin. In vivo suppression of lactate production or genetic depletion of lactate receptor GPR81 mitigates vascular permeability and multiple organ injury and improves survival outcome in polymicrobial sepsis. Our study reveals that metabolic cross-talk between glycolysis-derived lactate and the endothelium plays a critical role in the pathophysiology of sepsis.
Source: Science Advances
Authors: Kun Yang, Min Fan, Xiaohui Wang, Jingjing Xu, Yana Wang, P. Spencer Gill, Tuanzhu Ha, Li Liu, Jennifer V. Hall, David L. Williams, Chuanfu Li
Institutions: East Tennessee State University, Jiangsu Province Hospital
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,500
Awards: Role of Toll-Like Receptor Signaling in Cardiac Ischemia, Quillen College of Medicine Building 119 Renovation, Training Innate Immunity: A new approach to the treatment of Sepsis, Novel role of lactate in cardiac fibrosis after myocardial infarction, HSPA12B and YAP cooperatively regulate endothelial cell proliferation and angiogenesis after myocardial infarction., Novel Role of Lactate for Cardiovascular Dysfunction in Sepsis, Innate Immunity and Cardiovascular Function in Sepsis
OpenAlex ID: W4224948639