Pro-inflammatory activation of endothelial cells and its counter-regulation

In the setting of infection or wound healing, a tightly controlled pro-inflammatory and pro-thrombotic conversion of the endothelial phenotype is a beneficial biological response which helps to combat infection and renew organ integrity. However, prolonged endothelial activation, which has escaped control mechanisms of the host, may set off unfavorable sequelae, such as atherosclerosis and intravascular thrombosis (13). Factors responsible for endothelial homeostasis involve both biochemical and biomechanical stimuli. The former include inflammatory cytokines, namely tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β), both of them known also as “proximal” cytokines which, in their turn, induce endothelial expression of adhesion molecules (e.g., E-selectin, vascular cell adhesion molecule-1 or VCAM-1, intercellular adhesion molecule-1 or ICAM-1) and pro-coagulant factors, most importantly tissue factor (TF). The net result is known as endothelial dysfunction (12, 18). The central mediator which converges most inflammatory stimuli is the transcription factor nuclear factor κB (NF-κB). Its activation leads to the disruption of the noninflammatory, non-thrombogenic vascular lining, which is transformed into a pro-inflammatory, pro-thrombotic endothelial surface (16). On the other hand, biomechanical factors, namely laminar shear stress (LSS), induce the expression of various protective factors, the most prominent ones being endothelial NOS (eNOS) and thrombomodulin (TM). Both of them are essential for regulation of vascular tone and maintenance of the quiescent state of endothelial cells (4, 25). In those areas of the vasculature where laminar shear stress does not fit in with its physiological range, expression of NF-κB is substantially enhanced (10). Consequently, these vascular segments are prone to the development of atherosclerosis. For example, branch points of the vascular tree are exposed to chaotic blood flow patterns, which are entirely distinct from regular laminar shear stress. Therefore, these branch points are highly susceptible to the formation of atherosclerotic lesions (19).