Figure 1.
Endothelial mechanisms that maintain vascular quiescence and vessel patency. The quiescent endothelium depicted in the center of the figure features a rich glycocalyx covering its inner surface (black lines) and is surrounded by pericytes (dark green) on its out surface. Circulating cells move freely within its lumen. The endothelium has several receptor systems that mediate constitutive cytoprotective signaling (green background). (Panel 1) Activation of Tie2 (blue) by multimeric angiopoitein-1 (orange). Clustering of Tie2 by angiopoieitin-1 results in phosphorylation of the Tie2 cytoplasmic tail. Stimulation of Tie2 also promotes barrier function via activation of Rac1. (Panel 2) Although ACE produces angiotensin II, which can stimulate inflammatory signaling, the resting endothelium expresses ACE2, which cleaves angiotensin II into Ang(1-7). Ang(1-7) binds to MAS1, resulting in cytoprotective signaling. (Panel 3) The endothelium expresses thrombomodulin (TM), which binds thrombin (IIa) and occludes its fibrin binding site, modifying its substrate specificity. TM is closely associated with the endothelial protein C receptor (EPCR), which binds protein C (PC) enabling it to be cleaved by thrombin and generate activated protein C (APC). APC is a potent anticoagulant that cleaves factors Va and VIIIa. It also cleaves protease-activated receptor 1 (PAR1) at a noncanonical cleavage site, stimulating cytoprotective signaling. Antithrombotic mechanisms are indicated with yellow background. (Panel 4) The endothelium expresses tissue factor pathway inhibitor-β (TFPIβ), which associates with the membrane surface via a glycosylphosphatidylinositol (GPI) anchor. TFPIβ binds to both factor VIIa (FVIIa) and factor Xa (FXa) via its kunitz domains (red), thereby inhibiting the ability of tissue factor (TF) to activate coagulation. (Panel 5): Fibrin is cleared from the vasculature by plasmin degradation. Endothelial cells secrete both tissue plasminogen activator (tPA) and urokinase plasminogen activation (uPA), which binds to the urinokinase plasminogen activator receptor (uPAR). Plasminogen activators convert plasminogen to plasmin, which cleaves fibrin, resulting in generation of fibrin degradation products (FDPs) and d-dimer. Plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2) inhibit tPA and uPA. (Panel 6) Several surface proteins inhibit inappropriate complement activation. These include the type 1 membrane protein CD46 that inactivates C3b and C4b, the GPI-linked membrane protein CD55 (or complement decay-accelerating factor) that prevents formation of C3-convertase and C5-convertase, and the GPI-linked membrane protein CD59 that prevents C9 polymerization, thereby blocking formation of the membrane attack complex (MAC). (Panel 7) The endothelium also elaborates nitric oxide (NO) and PGI2 to maintain platelets in a resting state. These mechanisms maintain blood flow as depicted in the schematic of a resting venule in the center of the figure: endothelium (pink rectangular cells), glycocalyx (black), platelets (beige), neutrophils (pink nucleated cells), monocytes (irregular cells with purple nucleus), and lymphocytes (blue). (Panel 8) Healthy endothelium is coated with a thick glycocalyx consisting of heparan sulfate and chondroitin sulfate attached to syndecan, hyaluronan, and glypican-1. This physical barrier buffers oncotic forces across the vessel wall and limits interaction with leukocytes and platelets. (Panel 9) Maintenance of endothelial cell barrier function (orange background) is an active process. Fluid and leukocyte extravasation is prevented by tight junctions containing junctional adhesion molecules and claudins and adherens junctions containing VE-cadherin. Activation of Tie2 by Angpt-1 or the sphingosine 1-phosphate receptor 1 (S1PR1) by sphingosine 1-phosphate (S1P) maintains cortical actin networks and promotes VE-cadherin adherens junctions at the cell surface. Cytoprotective signaling through EPCR and Tie2 inhibits activation of the inflammatory and prothrombotic transcription factor NF-κB. Laminar blood flow activates transcription factors KLF2 and KLF4, which promote maintenance of vascular tone via expression of nitric oxide synthase and C-natriuretic peptide (CNP) and reduce inflammation and thrombosis by increasing Tie2 and TM expression. Tonic bradykinin (BK) signaling through the constitutive bradykinin receptor 2 (B2R) and Angiotensin1-7 (Ang1-7) activation of the Mas1 receptor promotes vascular tone via NO synthase and suppressing inflammation. ACE, angiotensin-converting enzyme.

Endothelial mechanisms that maintain vascular quiescence and vessel patency. The quiescent endothelium depicted in the center of the figure features a rich glycocalyx covering its inner surface (black lines) and is surrounded by pericytes (dark green) on its out surface. Circulating cells move freely within its lumen. The endothelium has several receptor systems that mediate constitutive cytoprotective signaling (green background). (Panel 1) Activation of Tie2 (blue) by multimeric angiopoitein-1 (orange). Clustering of Tie2 by angiopoieitin-1 results in phosphorylation of the Tie2 cytoplasmic tail. Stimulation of Tie2 also promotes barrier function via activation of Rac1. (Panel 2) Although ACE produces angiotensin II, which can stimulate inflammatory signaling, the resting endothelium expresses ACE2, which cleaves angiotensin II into Ang(1-7). Ang(1-7) binds to MAS1, resulting in cytoprotective signaling. (Panel 3) The endothelium expresses thrombomodulin (TM), which binds thrombin (IIa) and occludes its fibrin binding site, modifying its substrate specificity. TM is closely associated with the endothelial protein C receptor (EPCR), which binds protein C (PC) enabling it to be cleaved by thrombin and generate activated protein C (APC). APC is a potent anticoagulant that cleaves factors Va and VIIIa. It also cleaves protease-activated receptor 1 (PAR1) at a noncanonical cleavage site, stimulating cytoprotective signaling. Antithrombotic mechanisms are indicated with yellow background. (Panel 4) The endothelium expresses tissue factor pathway inhibitor-β (TFPIβ), which associates with the membrane surface via a glycosylphosphatidylinositol (GPI) anchor. TFPIβ binds to both factor VIIa (FVIIa) and factor Xa (FXa) via its kunitz domains (red), thereby inhibiting the ability of tissue factor (TF) to activate coagulation. (Panel 5): Fibrin is cleared from the vasculature by plasmin degradation. Endothelial cells secrete both tissue plasminogen activator (tPA) and urokinase plasminogen activation (uPA), which binds to the urinokinase plasminogen activator receptor (uPAR). Plasminogen activators convert plasminogen to plasmin, which cleaves fibrin, resulting in generation of fibrin degradation products (FDPs) and d-dimer. Plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2) inhibit tPA and uPA. (Panel 6) Several surface proteins inhibit inappropriate complement activation. These include the type 1 membrane protein CD46 that inactivates C3b and C4b, the GPI-linked membrane protein CD55 (or complement decay-accelerating factor) that prevents formation of C3-convertase and C5-convertase, and the GPI-linked membrane protein CD59 that prevents C9 polymerization, thereby blocking formation of the membrane attack complex (MAC). (Panel 7) The endothelium also elaborates nitric oxide (NO) and PGI2 to maintain platelets in a resting state. These mechanisms maintain blood flow as depicted in the schematic of a resting venule in the center of the figure: endothelium (pink rectangular cells), glycocalyx (black), platelets (beige), neutrophils (pink nucleated cells), monocytes (irregular cells with purple nucleus), and lymphocytes (blue). (Panel 8) Healthy endothelium is coated with a thick glycocalyx consisting of heparan sulfate and chondroitin sulfate attached to syndecan, hyaluronan, and glypican-1. This physical barrier buffers oncotic forces across the vessel wall and limits interaction with leukocytes and platelets. (Panel 9) Maintenance of endothelial cell barrier function (orange background) is an active process. Fluid and leukocyte extravasation is prevented by tight junctions containing junctional adhesion molecules and claudins and adherens junctions containing VE-cadherin. Activation of Tie2 by Angpt-1 or the sphingosine 1-phosphate receptor 1 (S1PR1) by sphingosine 1-phosphate (S1P) maintains cortical actin networks and promotes VE-cadherin adherens junctions at the cell surface. Cytoprotective signaling through EPCR and Tie2 inhibits activation of the inflammatory and prothrombotic transcription factor NF-κB. Laminar blood flow activates transcription factors KLF2 and KLF4, which promote maintenance of vascular tone via expression of nitric oxide synthase and C-natriuretic peptide (CNP) and reduce inflammation and thrombosis by increasing Tie2 and TM expression. Tonic bradykinin (BK) signaling through the constitutive bradykinin receptor 2 (B2R) and Angiotensin1-7 (Ang1-7) activation of the Mas1 receptor promotes vascular tone via NO synthase and suppressing inflammation. ACE, angiotensin-converting enzyme.

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