© 1996 American Heart Association, Inc.
Articles |
Endothelial Adhesion Molecules in Atherogenesis
A Concerto or a Solo?
Correspondence to Prof M.A. Vadas, Director, Hanson Centre for Cancer Research, Frome Road, Adelaide, South Australia, 5000.
Key Words: vascular cell adhesion molecule-1 • rolling • adhesion • adenovirus
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There have been a number of key discoveries over the last 10 years that provide an understanding of the development of the cellular events of the inflammatory response. These began with the demonstration that proinflammatory cytokines such as tumor necrosis factor-
and interleukin-1 induce endothelial cells to become adhesive for leukocytes1 2 and the subsequent discovery of the molecules responsible for this adhesiveness (eg, E-selectin, P-selectin, and vascular cell adhesion molecule-1 [VCAM-1]3 4 5 ). A flurry of publications examining the details of leukocyte-endothelial interactions followed, but a unifying concept putting these interactions into a physiological context was missing. A breakthrough came with the description of the "three-step-model" of the development of the inflammatory response by Butcher6 and Springer.7 This model placed the adhesive events in a logical order, related them to physiologically relevant conditions of flow, ascribed particular molecules to distinct cellular events (in other words, created order out of chaos), and was enthusiastically embraced by the workers in the field. The three steps enunciated were 1) capture of leukocytes from the axial stream to roll along the endothelium, 2) the firm adhesion of these leukocytes to endothelial cells, and 3) their subsequent transmigration into tissues. Rolling was shown to be mediated by E- and P-selectin on endothelial cells. These adhesion proteins were thought to have special structural (long stems) and ligand-recognition features (lectin-carbohydrate interactions) that made them uniquely suitable for the rapid on/off adhesion that is an essential feature of rolling. Firm adhesion was mediated by intercellular adhesion molecule-1 and VCAM-1 interacting with the leukocyte integrins. Finally, transmigration was thought to be due to chemokines, such as interleukin-8, MCP-1, or Eotaxin, which also served to locally activate the integrins to mediate firm adhesion.
Recently, several features of this model have been tested. On one hand, animals with genetic deletion of both P- and E-selectin have been found to have severe deficiencies in rolling and in developing inflammatory responses,8 suggesting the essential nature of these selectins. On the other hand, rolling has been shown to take place on VCAM-1 recognized by integrins,9 10 thus challenging the essential nature of selectins and suggesting considerable redundancy in the function of adhesion molecules. Berlin et al9 have also suggested that the location of adhesion molecules on tips of microvilli rather than their intrinsic nature was the key in supporting rolling.
The article by Gerszten et al11 in this issue of Circulation Research is relevant to this debate. Most of the earlier conclusions were based either on adhesion of cells to purified adhesion proteins attached to solid matrices or the use of blocking monoclonal antibodies to cytokine-stimulated endothelial cells or exteriorized microvessels. Gerszten et al argue that a clearer picture of the role of adhesion proteins can be obtained by using adenovirus vectors encoding a particular adhesion protein to transiently transduce endothelial cells. This system, in which virtually 100% of cells are transduced, is believed to avoid the activation of many signaling pathways and expression of many adhesion molecules, such as those seen after cytokine treatment. However, infection by a virally based vector will lead to changes in any cell. Controls for this type of confounding factor are by definition incomplete, because the full extent of perturbation of endothelial cells by adenovirus is unknown; furthermore, the "empty vector" is an insufficient control, because the confounding factor(s) may be revealed only by its action on the transduced adhesion protein. These considerations are especially relevant to adhesion proteins in which conformational changes, induced by cytoplasmic events or secreted products, can alter function. Moreover, adenoviruses use the functionally important vß5 and vß3 integrins to infect cells,12 and this may specifically alter cellular function. Indeed, changes in smooth muscle cell phenotype after adenovirus transfection have been described previously.13
The article by Gerszten et al11 is also relevant to atherosclerosis, because the particular adhesion protein they use is VCAM-1, one that is intensely expressed in atherosclerotic lesions (especially the vasa vasorum)14 and that supports the adhesion of the leukocytes, monocytes, and memory T cells, shown to be key participants in the atherosclerotic lesion.
Gerszten et al11 then found that human umbilical vein endothelial cells transduced with adenovirus vectors containing rabbit VCAM-1 do not express relevant amounts of other adhesion proteins and support the adhesion of T-cell tumor lines and memory T cells under conditions of modest (1.5 dyne/cm2) shear. This is an important finding that supports conclusions based on purified VCAM-1.9 10 However, Gerszten et al disagree with earlier work in that they observe no rolling of lymphocytes on the transduced cells. Given the paradigm that under flow, rolling is a prerequisite of firm adhesion, this is an important point of dissonance. The conclusion by Gerszten et al would have been strengthened by the demonstration that in an identical adenovirus system, E-selectin–transduced cells do support rolling and that similar densities of VCAM-1 that do support rolling were expressed on the transduced cells and on the matrices coated with purified VCAM-1.
The study of Gerszten et al11 may thus be important, first, because it provides a model for the study of leukocyte-endothelial interactions in which the expression of individual adhesion proteins can be manipulated, second, because it suggests that neovascular VCAM-1 can mediate leukocyte recruitment into plaques without the participation of other adhesion molecules, and third, because it challenges the three-step model for leukocyte adhesion/transmigration.
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References |
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TopIntroductionReferences |
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1. Gamble JR, Harlan JM, Klebanoff SJ, Vadas MA. Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci U S A. 1985;82:8667-8671.
2. Bevilacqua MP, Pober JS, Wheeler ME, Cotran RS, Gimbrone MA. Interleukin-1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes and related cell lines. J Clin Invest. 1985;76:2003.
3.
Bevilacqua MP, Stengelin S, Gimbrone MA Jr, Seed B. Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science.. 1989;243:1160.
4. Johnston GI, Cook RG, McEver RP. Cloning of GMP-140, a granule membrane protein of platelets and endothelium: sequence similarity to proteins involved in cell adhesion and inflammation. Cell.. 1989;56:1033-1044.[Medline] [Order article via Infotrieve]
5. Osborn L, Hession C, Tizard R, Vassallo C, Luhowskyj S, Chi-Rosso G, Lobb R. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell. 1989;59:1203.[Medline] [Order article via Infotrieve]
6. Butcher EC. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell. 1991;67:1033-1036.[Medline] [Order article via Infotrieve]
7. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994;76:301-314.[Medline] [Order article via Infotrieve]
8. Frenette PS, Mayadas TN, Rayburn H, Hynes RO, Wagner RO. Susceptibility to infection and altered hematopoiesis in mice deficient in both P- and E-selectins. Cell. 1996;84:563-574.[Medline] [Order article via Infotrieve]
9. Berlin C, Bargatze RF, Campbell JJ, von Andrian UH, Szabo MD, Hasslen SR, Nelson RD, Berg EL, Erlandsen SL, Butcher EC. Alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell. 1995;80:413-422.[Medline] [Order article via Infotrieve]
10.
Alon R, Kassner PD, Carr MW, Finger EB, Hemler ME, Springer TA. The integrin VLA-4 supports tethering and rolling in flow on VCAM-1. J Cell Biol. 1995;128:1243-1253.
11. Gerszten RE, Luscinskas FW, Ding HT, Dichek DA, Stoolman LM, Gimbrone MA Jr, Rosenzweig A. Adhesion of memory lymphocytes to vascular cell adhesion molecule-1–transduced human vascular endothelial cells under simulated physiological flow conditions in vitro. Circ Res. 1996; 79:1205-1215.
12.
Wickham TJ, Mathias P, Cheresh DA, Nemerow GR. Integrins vß3 and vß5 promoter adenovirus internalization but not virus attachment. Cell. 1993;73:309-319.[Medline]
[Order article via Infotrieve]
13. Newman KD, Dunn PF, Owens JW, Schulick AH, Virmani R, Sukhova G, Libby P, Dichek DA. Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia. J Clin Invest. 1995;96:2955-2965.
14. O'Brien KD, Allen MD, McDonald TO, Chait A, Harlan JM, Fishbein D, McCarty J, Ferguson M, Hudkins K, Benjamin CD, et al. Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques: implications for the mode of progression of advanced coronary atherosclerosis. J Clin Invest. 1993;92:945-951.
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