The focus of this article is an overview of the endothelial changes that initiate and perpetuate the process of atherogenesis. The endothelium can undergo a series of changes which allow it to participate in the inflammatory response; this is known as endothelial cell activation (ECA). The five core changes of ECA are loss of vascular integrity; expression of leucocyte adhesion molecules; change in phenotype from antithrombotic to prothrombotic; cytokine production, and upregulation of HLA molecules. The diverse effects of ECA share a common intracellular control mechanism through the activation of the transcription factors including Nuclear Factor kB. ECA is an initiating step in atherogenesis. Modified low density lipoproteins are probably the major cause of endothelial cell activation in atherogenesis, and become especially so after oxidation, glycation (in diabetes) or incorporation in immune complexes. In antiphospholipid syndrome (APS), antiendothelial cell antibodies have been detected in up to 67% of patients. In vitro studies suggest that aPL causes ECA and thus lead to speculation that aPL by causing ECA may initiate atherogenesis. Further clinical and in vitro studies are required to address these issues.
Willms-Kretschmer K , Flax MH , Cotran RS . The fine structure of the vascular response in hapten-specific delayed hypersensitivity and contact dermatitis . Lab Invest1967; 17: 334–349 .
2.
Pober J S . Cytokine-mediated activation of vascular endothelium . Am J Pathol1988; 133: 426–433 .
3.
Adams DH , Shaw S . Leucocyte-endothelial interactions and regulation of leucocyte migration . Lancet1994; 343: 831–836 .
4.
Bach FH , Robson SC , Winkler H et al. Barriers to xenotransplantation . Nature Med1995; 1: 869–873 .
5.
Mantovani A , Sozzani A , Vecchi A et al. Cytokine activation of endothelial cells: new molecules for an old paradigm . Thromb Haemost1997; 78: 406–414 .
6.
Pober JS , Orosz CG , Rose ML , Savage COCan graft endothelial cells initiate a host antigraft immune response?Transplantation1996; 61: 343–349 .
7.
De Waard V , van de Berg BMM , Veken J et al. Serial analysis of gene expression to assess the endothelial cell response to an atherogenic stimulus . Gene1999; 226: 1–8 .
8.
Baldwin AS . The NF-kB and 1kB proteins: new discoveries and insights . Ann Rev Immunol1996; 14: 649–681 .
9.
Brand K , Page S , Rogler G et al. Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion . J Clin Invest1996; 97: 1715–1722 .
10.
De Cataerina R , Libby P , Peng HB et al. Nitric oxide decreases cytokine-induced endothelial cell activation. Nitric oxide selectively reduces endothelial cell activation expression of adhesion molecules and proinflammaotry cytokines . J Clin Invest1995; 96: 60–68 .
11.
Rajavashisth TB , Yamada H , Mishra NK . Transcriptional activation of the MOSF gene by minimally modified LDL: involvement of NFkB . Arterioscler, Thromb Vasc Biol1995; 15: 1591–1598 .
12.
Meroni P , Khamashta MA , Younou P , Shoenfield Y . Mosaic of antiendothelial cell antibodies. Review of the first International Workshop on antiendothelial cell antibodies, clinical and pathological significance . Lupus1995; 4: 95–99 .
13.
Bierhaus A , Klevesath M , Illmer T et al. Ligands of RAGE mediate continuous NE-kB activation, that results in persistent endothelial tissue factor induction. Thromb Haemost1997; Suppl 1: 595-595.
14.
Chappell L,C , Seed PT , Briley A et al. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial . Lancet1999; 354: 810–816 .
15.
Ross R . The pathogenesis of atherosclerosis: a perspective for the 1990s . Nature1993; 362: 801–809 .
16.
Ross R . Atherosclerosis-an inflammatory disease . N Enql J Med1999; 340: 155–126 .
17.
Steinberg D . Low density lipoprotein oxidation and its pathobiological significance . J Biol Chem1997; 272: 20963–20966 .
18.
Libby P , Mach F , Schonbeck U et al. Regulation of the thrombotic potential of athermoa . Thromb Haem1999; 82: 736–741 .
19.
Westerman EM , Miles JM , Backonja M , Sundstrom WR . Neuropathological findings in multi-infarct dementia associated with anticardiolipin antibodies . Arthritis Rheum1992; 35: 1038–1041 .
20.
Creamer D , Black MM , Calonje E . Reactive angioendotheliomatosis in association with the antiphospholipid syndrome.
21.
Alarcon-Segovia D , Cardiel MH , Reyes E . Antiphospholipid arterial vasculopathy . J Rheumatol1989; 16: 762–767
22.
Drew P , Asherson RA , Zuk RJ et al. Aortic occlusion in systemic lupus erythematosis associated with antiphospholipid antibodies . Ann Rheum Dis1987; 46: 612–661 .
23.
Billingham ME . Histopathology of graft coronary disease . J Heart Lung Transplant1992; 11: S38–S44 .
24.
Salamon RN , Hughes CCW , Schoen FL . Huamn coronary transplantation associated arteriosclerosis: evidence for a chronic immune reaction to activated graft endothelial cells . Am J Pathol1990; 138: 791–798 .
25.
Dunn MJ , Crisp SJ , rose ML et al. Anti-endothelial antibodies and coronary artery disease after transplantation . Lancet1992; 339: 1566–1570 .
26.
Jurcervic S , Dunn MJ , Crisp S et al. A new ELISA to measure antiendothelial antibodies after cardiac transplantation demonstrates greater inhibition of antibody formation by tacrolimus compared with cyclopsporine . Transplantation1998; 65: 1197–1202 .
27.
Cervera R , Khamashta MA , Font J et al. Antiendothelial cell antibodies in patients with the antiphospholipid syndrome . Autoimmunity1991; 11: 1–6
28.
Hill MB , Phipps JL , Malia et al. Characterisation and specificity of anti-endothelial cell membrane antibodies and their relationship to thrombosis in the primary antiphospholipid syndrome . Clin Exp Immunol1995; 102: 368–372 .
29.
Simantov R , LaSala JM , Lo SK et al. Activation of cultured vascular endothelial cells by antiphospholipid antibodies . J Clin Invest1995; 96: 2211–2219 .
30.
Del Papa N , Guidali L , Sala A et al. Endothelial cells as targets for antiphospholipid antibodies . Arthritis Rheum1997; 40: 551–561 .
31.
Pierangeli SS , Colden-Stanfield M , Liu X et al. Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo . Circulation1999; 99: 1997–2002 .
32.
Blank M , Shoenfield Y , Cabilly S et al. Prevention of experimental antiphospholipid syndrome and endothelial cell activation by peptides . Proc Natl Acad Sci1999; 96: 5164–5168 .
33.
Roubey RAS . Immunology of the antiphospholipid antibody syndrome . Arthritis Rheum1996; 39: 1444–1456 .
34.
George J , Harats D , Gilburd B et al. Immunolocalization of b2-glycoprotein I tohuman atherosclerotic plaques . Circulation1999; 99: 2227–2230 .
35.
George J , Aprek A , Gilburd B et al. lnduction of early atherosclerosis in LDL receptor deficient mice immunised with b2 glycoprotein I . Circulation1998; 15: 1108–1115 .
36.
Barger AC , Beeuwkes R , Lainey LL , Silverman KJ . Vasa vasorum and neovascularisation of human coronary arteries . N Engl J Med1984; 310: 175–177 .
37.
Milei J , Parodi JC , Alonson GF et al. Carotid rupture and intraplaue haemorrhage: immunophenotyping and role of cells involved . Am Heart J1998; 136: 1096–1105 .
38.
Inuoe M , Itoh H , Ueda M et al. Vascular endothelial growth factor expression in human coronary atherosclerotic lesions: possible pathophysiological significance of VEGF in progression of atherosclerosis . Circulation1998; 98: 2108–2116 .
39.
Gould AL , Rossouw JE , Santanello NC et al. Cholesterol reduction yields clinical benefit. Impact of statin trials . Circulation1998; 97: 946–952
40.
Essig M Vrtovnik F , Nguyen G , Sraer JD , Friedlander C . Lovastatin modulates in vivo and in vitro thep lasminogen activator/plasmin system of rat proximal tubular cells: role of gen geranylation and Rho proteins . J Am Soc Nephrol1998; 9: 1385–1388 .
