Define endothelial activation

Learn More. The endothelium is now recognised as not simply being an inert lining to blood vessels, as thought in the s, but a highly specialised, metabolically active interface between blood and the underlying tissues—maintaining vascular tone, thromboresistance, and a selective permeability to cells and proteins. Moreover, under the stimulation of agents such as interleukin 1, the endothelium undergoes changes which allow it to participate in the inflammatory response; this is known as endothelial cell activation.

The term was coined in the s by Willms-Kretschmer. In the s an avalanche of papers showed that the newly discovered cytokines, interleukin 1 and tumour necrosis factor, changed surface molecules and thus the functions of cultured endothelial cells. To emphasise that these changes did not represent injury or dysfunction, Pober reintroduced the term endothelial cell activation. Activation entails a stereotyped series of processes, although their effects are diverse and are seen differently by specialists in different disciplines.

Immunologists study upregulation of surface antigens and adhesion molecules, while those in thrombosis research assess prothrombotic endothelial cell changes, and vascular biologists study changes in tone. All these effects, however, are components of endothelial cell activation and mutually interact in causing local inflammation.

The five core changes of endothelial cell activation are loss of vascular integrity; expression of leucocyte adhesion molecules; change in phenotype from antithrombotic to prothrombotic; cytokine production; and upregulation of HLA molecules. Loss of vascular integrity can expose subendothelium and cause the efflux of fluids from the intravascular space. Two stages of endothelial cell activation exist 4 ; the first, endothelial cell stimulation or endothelial cell activation type I, does not require de novo protein synthesis or gene upregulation and occurs rapidly.

Effects include the retraction of endothelial cells, expression of P selectin, and release of von Willebrand factor. The second response, endothelial cell activation type II, requires time for the stimulating agent to cause an effect via gene transcription and protein synthesis. The genes involved are those for adhesion molecules, cytokines, and tissue factor.

So what do we gain from understanding endothelial cell activation? It seems to be a common pathogenic mechanism for it is induced by a wide range of agents such as certain bacteria and viruses, interleukin 1 and tumour necrosis factor, physical and oxidative stress, oxidised low density lipoproteins, 8 and antiendothelial cell antibodies found in systemic autoimmune diseases such as the vasculitides, systemic lupus erythematosis, and antiphospholipid syndrome 9.

Tumor necrosis factor TNF is the prototypic proinflammatory cytokine and endothelial cells are the principal cellular targets of its actions.

Here I review the responses of endothelial cells to TNF, with emphasis on the induction of endothelial leukocyte adhesion molecules. I focus on the biochemistry and cell biology of signal transduction in TNF-treated endothelial cells that lead to the expression of adhesion molecules. Inflammation, defined as the local recruitment and activation of leukocytes, is an essential component of the innate immune response to pathogens and damaged cells.

The innate inflammatory response has only a limited ability to distinguish normal from infected or damaged cells. Consequently, injury to healthy bystander cells at a site of inflammation is common. Moreover, unresolved inflammation can itself become a disease process, a clear example being rheumatoid arthritis.

Inhibition of inflammation in such settings has become a primary goal of therapy irrespective of the underlying cause of the disease. For this reason, it is important to understand how inflammation develops and how it is regulated. In this chapter, I describe how tumor necrosis factor TNF , an important mediator of innate inflammation, acts on vascular endothelial cells ECs to promote the inflammatory response.

A description of the inflammatory response to injured tissues at the level of light microscopy was first made over years ago [ 2 ]. In those pioneering studies, Cohnheim noted that margination of leukocytes along the luminal surface of the postcapillary venule is the prelude to extravasation. Before the s, these events were generally interpreted as a response of circulating leukocytes to chemoattractant substances elaborated within the tissue, either by infectious microbes e.

N -formyl peptides or by the innate response e. Margination was explained by the observation that such substances not only induced chemotaxis but also triggered adhesion to endothelium, although the increase in adhesion was usually quite small not more than twofold [ 4 ].

This model did not explain why superfusion of chemotactic substances does not cause circulating leukocytes to adhere to endothelium until they reach the venules [ 5 ]. A re-evaluation of this paradigm began in the mid s with the finding that exposure of ECs to cytokines, such as IL-1 or TNF, caused the ECs to bind 20 to 40 times as many leukocytes as untreated ECs, dwarfing the effects of chemotaxins [ 6 ].

The change in EC adhesivity arose from the induction of new surface proteins, collectively designated as endothelial leukocyte adhesion molecules ELAMs , that bind counter-receptor proteins expressed on leukocytes [ 7 ]. Cytokine-treated ECs are also a source of chemoattractant cytokines chemokines that contribute to adhesion by activating the affinity of leukocyte counter-receptors for ELAMs [ 7 ]. These observations, combined with new experimental models such as parallel plate flow chambers and ex vivo videomicroscopy, led to the current multistep model of leukocyte recruitment centered on the responses of the vascular ECs lining postcapillary venules rather than on responses of leukocytes [ 8 , 9 ].

In brief, resting ECs are now viewed as noninteractive with leukocytes, so that random encounters with circulating white cells are short-lived, leaving both cells unaltered. Microbes and other inflammatory stimuli induce resident macrophages to release cytokines such as TNF or IL-1, which induce venular ECs to synthesize and express new proteins on their luminal cell surface.

Cytokine-activated ECs also synthesize, secrete, and display in association with cell-surface proteoglycans chemokines on their luminal surface. Shear force, imparted by flowing blood, causes these interactions to be rapidly broken, only to reform rapidly as the leukocyte is displaced. Multiple iterations of these processes results in rolling of the leukocyte on the EC surface. Rolling, but not free-flowing, leukocytes encounter and respond to the surface-displayed chemokines, causing cell spreading and clustering of surface integrins such as LFA-1 and VLA-4 at the contact area with the ECs.

Bound chemokines also stimulate leukocyte chemokinesis, resulting in crawling on the EC surface. As crawling leukocytes reach the junction between ECs, they extravasate through the junction into the tissue space, resulting in inflammation. Several refinements of this EC-based model of inflammation are worth noting.

One point involves the specialized nature of venular ECs. However, in certain disease states e. In addition, the patterns of adhesion molecule expression and chemokine expression are dynamic. For example, expression of E-selectin, associated with neutrophil extravasation, peaks early at 2—4 hours after TNF addition, corresponding to the onset of neutrophil recruitment.

VCAM-1, which is more closely associated with binding of mononuclear leukocytes, typically peaks at later times 12—24 hours after TNF addition, corresponding to the onset of T-cell recruitment [ 12 ]. These alterations in the EC surface produce corresponding changes in the nature of the inflammatory leukocyte populations that are recruited. In other words, the spatial, temporal, and qualitative patterns of EC adhesion molecule expression govern the location, evolution, and nature of the inflammatory response.

A central role of TNF in inflammation has been established by observations that many inflammatory reactions are impaired in TNF or TNF-receptor TNFR knockout mice [ 16 ] and that, in humans, TNF inhibitors soluble receptors or neutralizing antibodies are effective anti-inflammatory therapeutics [ 17 ]. In general, these changes are initiated by new gene transcription [ 7 ].

Signaling is initiated when ligand-occupied receptors recruit the binding of intracellular adaptor proteins to the intracellular portions of the receptor molecules reviewed in [ 20 , 21 ].

The mechanism of action of RIP is unclear; kinase-inactive RIP can function when overexpressed, but this may involve recruitment of endogenous RIP molecules with an intact kinase activity. The TRAF domains mediate both self-association and binding to adaptor proteins e. JNK-1 and -2 phosphorylate the transactivating domain of c-Jun, a component of AP-1, and thereby enable AP-1 to activate gene transcription.

The transcriptional potential of ATF2, like that of c-Jun, can be increased by phosphorylation of its transactivating domain, catalyzed by p38 MAP kinase. However, while overexpression of a c-Jun mutant that cannot be phosphorylated or of dominant negative JNK isoforms will inhibit E-selectin transcription, a mutant form of ATF2 that cannot be phosphorylated is not inhibitory [ 51 ].

The steric positioning of individual transcription factors bound to DNA, which permits coordinate interactions with coactivators, may depend upon DNA bending, controlled by proteins such as the high-mobility-group protein HMG-Y1 [ 43 — 45 ]. The basic unit of such coordinated complexes has been called an 'enhanceosome'.

Once the gene turns off, E-selectin cannot be effectively reinduced by TNF without a rest period of 18—24 hours. My laboratory has shown that the Akt and ceramide pathways do not contribute to adhesion molecule expression in ECs [ 63 , 64 ]. The biochemical view of TNF signaling described above is well supported by genetic and molecular data. Proper endothelial function is critical for vascular health, and endothelial dysfunction causes or contributes to numerous diseases.

Endothelial activation is a type of endothelial dysfunction that describes the process by which blood-borne and environmental stimuli cause endothelial cells to undergo dramatic functional changes. The vascular endothelium is a monolayer of cells that lines the entire luminal surface of the vasculature and forms a regulatory interface between circulating blood components and underlying tissue compartments.

The vascular endothelium covers a network of blood vessels that exceeds , km in aggregate length, with a surface area of approximately 5, m 2 De Caterina et al. Its massive size and distribution into all Skip to main content Skip to table of contents.

This service is more advanced with JavaScript available. Encyclopedia of Medical Immunology Edition. Editors: Ian R. Mackay, Noel R. Rose, Betty Diamond, Anne Davidson. Contents Search. Mechanisms of Endothelial Activation. Authors Authors and affiliations Matthew S. Waitkus Daniel P. Harris Paul E. Reference work entry First Online: 10 September How to cite.

Synonyms Endothelial cell activation; Endothelial dysfunction; Vascular endothelium.