Permeability of the Endothelial Barrier: Identifying and Reconciling Controversies

• Published in: Trends in molecular medicine Vol. 27; no. 4; pp. 314 - 331
• Main Authors: Claesson-Welsh, Lena, Dejana, Elisabetta, McDonald, Donald M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2021
• Subjects: Animals; Capillary Permeability - physiology; endothelial barrier function; endothelial cell junctions; Endothelial Cells - metabolism; Endothelial Growth Factors - metabolism; Endothelium, Vascular - physiology; G protein-coupled receptors; gap formation; Humans; Intercellular Junctions; postcapillary venules; Receptors, Opioid - metabolism; Receptors, Vascular Endothelial Growth Factor - metabolism; rho GTP-Binding Proteins - metabolism; Rho GTPases; Signal Transduction; Vascular Endothelial Growth Factor A - metabolism; VEGF receptors; endothelial barrier function; endothelial cell junctions; G protein-coupled receptors; Rho GTPases; VEGF receptors; gap formation; postcapillary venules
• ISSN: 1471-4914; 1471-499X; 1471-499X
• DOI: 10.1016/j.molmed.2020.11.006

Leakage from blood vessels into tissues is governed by mechanisms that control endothelial barrier function to maintain homeostasis. Dysregulated endothelial permeability contributes to many conditions and can influence disease morbidity and treatment. Diverse approaches used to study endothelial permeability have yielded a wealth of valuable insights. Yet, ongoing questions, technical challenges, and unresolved controversies relating to the mechanisms and relative contributions of barrier regulation, transendothelial sieving, and transport of fluid, solutes, and particulates complicate interpretations in the context of vascular physiology and pathophysiology. Here, we describe recent in vivo findings and other advances in understanding endothelial barrier function with the goal of identifying and reconciling controversies over cellular and molecular processes that regulate the vascular barrier in health and disease. In the microcirculation, endothelial permeability varies from least in arterioles to greatest in venules and is regulated in an organ-specific manner to control the extravasation of fluid, solutes, and large molecules.Inflammatory factors increase vascular permeability by inducing the formation of focal endothelial gaps that can be transient in acute inflammation or sustained in chronic conditions.Gap formation requires changes in the organization of tight junctions and adherens junctions that join endothelial cells and create a barrier.Adherens junction opening requires phosphorylation, loss of homophilic interactions, and internalization of VE-cadherin accompanied by changes in the cortical cytoskeleton.Sustained hyperpermeability in pathologic conditions can lead to edema, reduced vascular perfusion, impaired drug delivery, and exaggerated disease severity.