Destabilization of endothelial cell‐cell contacts modifies inflammatory responses

Abstract

Changes in the stability of endothelial cell‐cell contacts are commonly associated with chronic and acute vascular inflammation. However, it remains unclear how changes in endothelial cell‐cell contact impact the progress of vascular inflammation. KRIT1‐deficient animals lack the adherens junction accessory protein KRIT1, and exhibit a loss of cell‐cell contact stability. Krit1+/‐ mice exhibit increased baseline microvessel permeability, but maintain normal leukocyte responses. Stimulation of Krit1+/‐ mice with various inflammatory mediators enhanced edema formation but not leukocyte activation. Krit1+/‐ mice exhibited relatively normal leukocyte responses to TNF‐α, IL‐1β, and histamine, but, notably, Krit1+/‐ vessels did not become more permeable following TNF‐a treatment, contrary to what was seen in littermate controls. Though TNF‐α signaling in KRIT1 deficient endothelial cells appeared normal, these cells displayed increased oxidative stress, and treatment with TNF‐α failed to enhance reactive oxygen species (ROS) levels. In vivo, targeted inhibition of endothelial ROS was sufficient to restore microvascular permeability in Krit1+/‐ mice to WT levels. However, antioxidant treatment of TNF‐α‐treated WT and Krit1+/‐ animals reversed only venular permeability. KRIT1 depletion‐induced oxidative stress could be reversed by treatment with an NADPH‐oxidase inhibitor, suggesting that TNF‐α driven induction of NADPH oxidase may be inoperative in the absence of KRIT1. Thus, destabilization of endothelial adherens junctions following depletion of KRIT1 plays a vascular bed‐dependent role in modifying the vascular response to inflammation.