Endothelial injury in the initiation and progression of vascular disorders

Abstract

Endothelial cell dysfunction is considered to be an early event which subsequently leads to vascular wall disorders. Ultrastructural studies indicate that the endothelial cell changes involve membrane damage, increased permeability, swelling and necrosis. The endothelial cell loss of function could be as a result of changes in hemodynamic forces (shear and/or hoop stress), direct drug-induced cytotoxicity, mechanical device implant-induced injury and/or immune-mediated mechanisms. Drugs may perturb endothelial cell integrity by directly triggering inflammatory signaling cascades, enhancing expression of cellular adhesion molecules, activation of cytotoxic T cells and/or autoantibodies directed against endothelial cell membranes. Local release of inflammatory cytokines and chemokines activate endothelial cells to upregulate soluble adhesion molecules, activate neutrophils and generate reactive oxygen species which serve to amplify the initial inflammation leading to dysregulated apoptosis, secondary necrosis and overt vascular injury lesions. Considering the role of the endothelium in the initiation and propagation of vascular wall injury, there is a need for the discovery of validated biomarkers to serve as a predictor of activation of inflammatory cascades in the development of vascular injury. This article reviews some aspects of the multifaceted mechanisms that lead to the initial endothelial cell disruption and subsequent vascular wall injury.

Introduction

The endothelium participates actively in homeostatic mechanisms such as the regulation of vascular tone, maintenance of a non-thrombotic environment and in directing biological responses such as leukocyte trafficking to inflammatory sites (Argenbright and Barton, 1992, Harper and Savage, 1999, Widlansky, 2003). Endothelial cell participates through the expression of constitutive or induced molecules on its surface, and the synthesis and secretion of soluble mediators bound to or released from the cell surface. The vascular endothelium synthesizes nitric oxide (NO), prostaglandins, endothelium-derived hyperpolarizing factor (EDHF), endothelin and a range of other substances responsible for vascular homeostasis including smooth muscle tone, antiproliferative effects, vascular permeability and cellular adhesion molecules (Widlansky, 2003, Lum and Roebuck, 2001, Blann et al., 2005). In addition to regulating vascular tone, endothelial cells regulate leukocytes entering during basal, immune reactions and inflammation by responding to chemokines that modify expression of adhesion molecules. The involvement of various agents to induce vascular injury could be provoked either by direct cytotoxicity, induction of an immune process or expression of adhesion molecules (Harper and Savage, 1999, Coll-Vinent et al., 1998, Heeringa et al., 2005).

The endothelium comprises the largest homogenous surface of the body for actively mediating the immune defense. Immunologically mediated endothelial cell activation has been implicated as an important process in the initiation of vascular injury (Blann et al., 2005, Cines et al., 1998, Constans and Conri, 2006). Studies have shown that activated endothelial cells participate in T cell-mediated immune reactions and also serve as antigen-specific cells (Matsuki et al., 2005, Pober et al., 2001). The antigens on the activated endothelial cells interact with CD4 and CD8 T lymphocytes to propagate cell-mediated immune responses (Pober et al., 2001). Moreover, activated endothelial cells upregulate the expression of major histocompatibility complex (MHC) encoded molecules (Pober et al., 2001). Upon activation, endothelial cells express a number of immunologically relevant surface molecules such as adhesion molecules of the immunoglobulin gene superfamily as well as secrete cytokines and growth factors (Blann et al., 2005). Secreted cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNFα) and interferon (IFNγ) induce the secretion of MHC class I antigens. The latter can activate neutrophils and trigger an acute inflammatory cascade which subsequently leads to endothelial cell injury (Heeringa et al., 2005, Bratt and Palmblad, 1997). These events alter the morphology of the membrane, cytoskeleton structure and cell matrix organization leading to permeability of molecules. It has been demonstrated that cytokine-dependent stimulation of endothelial cell activates cytotoxic capacity of polymorphonuclear leukocytes (Argenbright and Barton, 1992, Matsuki et al., 2005). This process depends on the expression of adhesion molecules including intracellular adhesion molecule-1 (ICAM), E-selectin and vascular cell adhesion molecule-1 (VCAM) which are sequentially upregulated and enhance the recruitment of neutrophils (Bratt and Palmblad, 1997). Thus, endothelial dysfunction is integrally associated with inflammatory events which culminate in vascular injury (Harper and Savage, 1999, Widlansky, 2003, Constans and Conri, 2006) (Fig. 1).