Extracellular matrix, junctional integrity and matrix metalloproteinase interactions in endothelial permeability regulation

Abstract

Vascular endothelial permeability is maintained by the regulated apposition of adherens and tight junctional proteins whose organization is controlled by several pharmacological and physiological mediators. Endothelial permeability changes are associated with: (1) the spatial redistribution of surface cadherins and occludin, (2) stabilization of focal adhesive bonds and (3) the progressive activation of matrix metalloproteinases (MMPs). In response to peroxide, histamine and EDTA, endothelial cells sequester VE-cadherin and alter its cytoskeletal binding. Simultaneously, these mediators enhance focal adhesion to the substratum. Oxidants, cytokines and pharmacological mediators also trigger the activation of matrix metalloproteinases (MMPs) in a cytoskeleton and tyrosine phosphorylation dependent manner to degrade occludin, a well-characterized tight junction element. These related in vitro phenomena appear to co-operate during inflammation, to increase endothelial permeability, structurally stabilize cells while also remodelling cell junctions and substratum.

Fig. 1

Junctions, focal adhesions and permeability regulation. The model proposed in this review suggests that permeability is regulated by events that include the focal adhesion plaque and cytoskeleton-dependent activation of kinases, particularly FAK and MAPKs. The activation of MAPKs triggers alterations in the assembly of tight junctions, but probably also influences adherens junctional stability. The signals transduced by focal adhesive signalling scaffolds may further affect the presentation of cadherins. Protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP) activated through these scaffolds likely govern adherens and tight junction organization via enhanced kinase activity (solid red lines) and phosphatase inhibition (broken red lines).

Fig. 2

Signalling and structural interactions in inflammation. Inflammatory microvascular permeability is induced acutely by activation of receptor, oxidants, and chronically by proteases like MMPs and elastase which are derived from leucocytes, adventitial cells and endothelial cells. Cytokines can also induce endothelial MMP synthesis and activation. Acutely, receptor-mediated, g-protein-linked activation of multiple kinases promote alterations in junction-linker protein-cytoskeletal binding and also stimulate cytoskeletal retraction. Active MMPs and other proteases will degrade components of both extracellular matrix and junctions, decreasing both junctional bonds and restrictive properties of the matrix. Activation of kinases may also affect junction bonds by altering the spatial distribution of junctional proteins. Together these changes in junctional organization help to promote the increased vascular permeability seen during inflammation.