Endothelium--role in regulation of coagulation and inflammation

Abstract

By its strategic position at the interface between blood and tissues, endothelial cells control blood fluidity and continued tissue perfusion while simultaneously they direct inflammatory cells to areas in need of defense or repair. The endothelial response depends on specific tissue needs and adapts to local stresses. Endothelial cells counteract coagulation by providing tissue factor and thrombin inhibitors and receptors for protein C activation. The receptor PAR-1 is differentially activated by thrombin and the activated protein C/EPCR complex, resulting in antithrombotic and anti-inflammatory effects. Thrombin and vasoactive agents release von Willebrand factor as ultra-large platelet-binding multimers, which are cleaved by ADAMTS13. Platelets can also facilitate leukocyte-endothelium interaction. Platelet activation is prevented by nitric oxide, prostacyclin, and exonucleotidases. Thrombin-cleaved ADAMTS18 induces disintegration of platelet aggregates while tissue-type plasminogen activator initiates fibrinolysis. Fibrin and products of platelets and inflammatory cells modulate the angiogenic response of endothelial cells and contribute to tissue repair.

Fig. 1

Adaptation of endothelial cells to inflammatory stimuli and hypoxia. Upper part, the classical (canonical) NFκB pathway is activated by various mediators and their receptors and involves liberation of the NFκB (p65/p50) after phosphorylation and degradation of IκBα, -β, and -ε (indicated as IκBα). In addition, lymphotoxin and CD40 ligand can further influence endothelial activation probably via the non-canonical NFκB pathway or part of it. Further details are given in the text. Lower part, left, the two prolines of the α-subunits of HIF-1 and HIF-2 are hydroxylated by proline hydoxylase-2 (PHD-2), which requires oxygen (O ₂), after which they bind do von Hippel–Lindau (VHL) protein and are degraded in the proteasome. The lack of oxygen (lower part, right) causes rescue of the α-subunits of HIF-1 and HIF-2, which—after nuclear entry—each dimerize with HIF1β and activate numerous genes. The endothelial response varies with that of many other cells as both HIF1 and HIF2 become active, while most tissue cells express only HIF1 subunits. Hypoxia can also induce unfolded protein stress, which via activation of IRE1 and subsequent steps can activate IKK and subsequently NFκB. Abbreviations: NOX NADPH oxidase; other abbreviations are given in the text

Fig. 2

Effects of thrombin on endothelial cell regulation of hemostasis. Abbreviations: TM thrombomodulin, APC activated protein C, ATIII antithrombin III, PAR-1 protease-activated receptor-1, EPCR endothelial protein C receptor, t-PA tissue-type plasminogen activator, WPB Weibel–Palade body, VWF von Willebrand factor, ULVWF ultra-large VWF, ADAMTS18 a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 18, C-terminal carboxy-terminal, NO nitric oxide, eNOS endothelial NO synthase, PGI2 prostacyclin, PGE2 prostaglandin E2