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Endothelial cell activation

BMJ 1998; 316 doi: (Published 02 May 1998) Cite this as: BMJ 1998;316:1328

A central pathophysiological process

  1. Beverley J Hunt, Consultant,
  2. Karen M Jurd, Honorary lecturer
  1. Departments of Haematology and Rheumatology, Guy's and St Thomas's Trust, London SE1 7EH
  2. Department of Haematology, Guy's and St Thomas's Trust, London SE1 7EH

    The endothelium is now recognised as not simply being an inert lining to blood vessels, as thought in the 1960s, 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 1960s by Willms-Kretschmer.1 He noted that in delayed hypersensitivity reactions the endothelium became plump and leaky and displayed increased quantities of biosynthetic organelles such as endoplasmic reticulum.1 He used the term activated to imply a change in function as well as morphology. In the 1980s 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.2

    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. Upregulation of leucocyte adhesion molecules such as E-selectin, ICAM-1, and VCAM-1 allows leucocytes to adhere to endothelium and then move into the tissues.3 The prothrombotic effects of endothelial cell activation include loss of the surface anticoagulant molecules thrombomodulin and heparan sulphate; reduced fibrinolytic potential due to enhanced plasminogen activator inhibitor type 1 release; loss of the platelet antiaggregatory effects of ecto-ADPases and prostacyclin; and production of platelet activating factor, nitric oxide, and expression of tissue factor.4 Cytokines are synthesised, including interleukin 6, which regulates the acute phase response, and chemoattractants such as interleukin 8 and monocyte chemoattractant protein 1.5 Expression of class II HLA molecules allows endothelial cells to act as antigen presenting cells, especially important in transplant rejection.6

    Two stages of endothelial cell activation exist4; 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.

    Our growing understanding of intracellular signalling has led to the discovery that the diverse effects of endothelial cell activation share a common intracellular control mechanism through the activation of the transcription factors, including nuclear factor κB.7 A stimulating agent acting at the endothelial cell surface causes the activation of cytoplasmic nuclear factor κB. Once activated, nuclear factor κB is transported into the nucleus and binds to promoter areas of genes which are upregulated in endothelial cell activation.

    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 syndrome9). Endothelial cell activation is a graded rather than an all or nothing response—for example, changes in endothelial cell integrity range from simple increases in local permeability to major endothelial cell contraction, exposing large areas of subendothelium. Activation may occur locally, as in transplant rejection,4 or systemically, as in septicaemia and the systemic inflammatory response. In atherosclerosis endothelial cell activation may mediate the deposition of atheroma for oxidised low density lipoprotein causes endothelial cell activation. In vitro advanced glycation end products mediate prolonged activation of nuclear factor κB, thus tantalisingly suggesting that vascular diabetic complications may be due to chronic endothelial cell activation.10 The picture is incomplete as yet, for some mechanisms of endothelial cell activation have been observed only in vitro or in animals.

    The discovery of the intracellular mechanisms of endothelial cell activation have thrown light on how some long established treatments work. Some of the antiinflammatory effects of glucocorticoids11 and aspirin12 act through inhibition of nuclear factor κB. As a transcriptional activator of the genes of endothelial cell activation, nucear factor κB itself is an interesting target for pharmacological manipulation, and fundamental approaches to switching it off are being explored. This may provide novel therapeutic avenues for inflammatory conditions.


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