Endothelial cell response in sepsis. (a) Leukocyte trafficking. Activated endothelial cells (red-colored cells) express increased levels of E-selectin, P-selectin, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 (all but P-selectin are shown). Upregulation of E-selectin, ICAM-1 and VCAM-1 are mediated at a transcriptional level (activation signal and promoter with transcriptional start site are shown in the inset). E selectin induces rolling of circulating leukocytes. VCAM-1 and ICAM-1 induce firm adhesion of leukocytes by binding to very late antigen 4 (VLA4) and leukocyte function antigen LFA1, respectively. Following firm adhesion, leukocytes transmigrate through and/or between endothelial cells into the underlying tissue (not shown). In sepsis, E-selectin, ICAM-1, and VCAM-1 are cleaved from the cell surface and circulate as a soluble form of the receptor. Circulating levels are indirect measures of the degree of endothelial activation. (b) Hemostasis. Activated endothelial cells undergo a net shift in hemostatic balance towards the procoagulant side, leading to local clot formation. During fibrinolysis tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) mediate the conversion of plasminogen to plasmin. Plasmin, in turn, proteolytically degrades fibrin. Activated endothelial cells express increased levels of plasminogen activator inhibitor (PAI-1), which inhibit the activity of t-PA and u-PA, thus accentuating the procoagulant state. (c) Vascular endothelial growth factor (VEGF) signaling. Under normal conditions (quiescence), VEGF signaling plays a critical role in homeostasis. VEGF binds to two receptors on endothelial cells, VEGF receptor (VEGFR) 1 and 2. VEGFR1 is also known as Flt-1. In sepsis (activated state), circulating levels of VEGF are increased. Elevated VEGF signaling, in turn, leads to increased vascular leak, leukocyte adhesion/trafficking, and clot formation. Sepsis is also associated with increased circulating levels of a soluble form of VEGFR1 (sFlt-1). sFlt-1 binds VEGF in the blood, thus acting as a competitive inhibitor of VEGF signaling in endothelial cells. Sepsis-mediated induction of sFlt-1 may represent a critical component of the host anti-inflammatory response.