Circulating endothelial cells in acute ischaemic stroke

Summary

Increased numbers of CD146-bearing circulating endothelial cells (CECs) in the peripheral blood probably represent the most direct evidence of endothelial cell damage. As acute ischaemic strokes are associated with endothelial abnormalities, we hypothesised that these CECs are raised in acute stroke, and that they would correlate with the other indices of endothelial perturbation, i.e. plasma von Willebrand factor (vWf) and soluble E-selectin. We studied 29 hypertensive patients (19 male; mean age 63 years) who presented with an acute stroke and compared them with 30 high risk hypertensive patients (21 male; mean age 62 years) and 30 normotensive controls (16 male; mean age 58 years). CECs were estimated by CD146 immunobead capture, vWf and soluble E-selectin by ELISA. Patients with an acute ischaemic stroke had significantly higher numbers of CECs/ml of blood (p<0.001) plasma vWf (p=0.008) soluble E-selectin (p=0.002) and higher systolic blood pressure (SBP) as compared to the other groups. The number of CECs significantly correlated with soluble E-selectin (r=0.432, p<0.001) and vWf (r=0.349, p=0.001) but not with SBP (r=0.198, p=0.069). However, in multivariate analysis, only disease group (i.e. health, hypertension or stroke) was associated with increased CECs. Acute ischaemic stroke is associated with increased numbers of CECs. The latter correlate well with established plasma markers of endothelial dysfunction or damage, thus unequivocally confirming severe vasculopathy in this condition. However, the greatest influence on CECs numbers was clinical group.

Keywords

Endothelial damage - acute ischaemic stroke - hypertension - circulating endothelial cells - CD146

• References

• 1 Lee AJ. The role of rheology and haemostatic factors in hypertension. J Human Hypertens 1997; 11: 767-76.
• 2 Lane DA, Wolff S, Ireland H. et al. Activation of coagulation and fibrinolytic systems following stroke. Br J Haematol 1983; 53: 655-8.
• 3 Lip GYH, Blann AD, Farooqi I S. et al. Abnormal haemorheology, endothelial function and thrombogenesis in relation to hypertension in acute (ictus <12 hours) stroke patients. Blood Coagul Fibrinolysis 2001; 12: 307-15.
• 4 Bath PMW, Blann A, Smith N. et al. Von Willebrand factor, P-selectin and fibrinogen levels in patients with acute ischaemic and haemorrhagic stroke, and their relationship with stroke subtype and functional outcome. Platelets 1998; 9: 155-9.
• 5 Liu L, Lin Z, Shen Z. Changes in von Willebrand factor and antithrombin III levels in acute stroke: difference between thrombotic and haemorrhagic stroke. Thromb Res 1993; 72: 353-8.
• 6 Felmeden DC, Spencer CG, Chung N A. et al. Relation of thrombogenesis in systemic hypertension to angiogenesis and endothelial damage/dysfunction (a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)). Am J Cardiol 2003; 92: 400-5.
• 7 Widlansky ME, Gokce N, Keaney Jr. JF. et al. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003; 42: 1149-60.
• 8 Woywodt A, Bahlmann FH, De Groot K. et al. Circulating endothelial cells: life, death, detachment and repair of the endothelial cell layer. Nephrol Dial Transplant 2002; 17: 1728-30.
• 9 Mutin M, Canavy I, Blann A. et al. Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells. Blood 1999; 93: 2951-8.
• 10 Woywodt A, Streiber F, De Groot K. et al. Circulating endothelial cells as markers for ANCA-associated small-vessel vasculitis. Lancet 2003; 361: 206-10.
• 11 Woywodt A, Scheer J, Hambach L. et al. Circulating endothelial cells as a marker of endothelial damage in allogeneic hematopoietic stem-cell transplantation. Blood 2004; 103: 3603-5.
• 12 Makin AJ, Blann AD, Chung N A. et al. Assessment of endothelial damage in atherosclerotic vascular disease by quantification of circulating endothelial cells; Relationship with von Willebrand factor and tissue factor. Eur Heart J 2004; 25: 371-6.
• 13 Bull TM, Golpon H, Hebbel R P. et al. Circulating endothelial cells in pulmonary hypertension. Thromb Haemost 2003; 90: 698-703.
• 14 Folkow B. Hypertension and endothelial dysfunction – aspects of atheroma protection. Blood Pressure. 1992 01 11-12.
• 15 Drexler H. Endothelial dysfunction: clinical implications. Prog Cardiovasc Dis 1997; 4: 287-324.
• 16 Blann AD, Lip GY. The endothelium in atherothrombotic disease: assessment of function, mechanisms and clinical implications. Blood Coagul Fibrinolysis 1998; 9: 297-306.
• 17 Felmeden DC, Blann AD, Spencer C G. et al. A comparison of flow-mediated dilatation and von Willebrand factor as markers of endothelial cell function in health and in hypertension: relationship to cardiovascular risk and effects of treatment. Blood Coagul Fibrinolysis 2003; 14: 425-31.
• 18 Lee KW, Lip GY, Tayebjee M. et al. Circulating endothelial cells, Von Willebrand Factor, interleukin-6 and prognosis in patients with acute coronary syndromes. Blood 2005; 105: 526-32.
• 19 Quilici J, Banzet N, Ambrosi P. et al. Circulating endothelial cell count as a diagnostic marker for non-ST elevation acute coronary syndromes. Circulation 2004; 110: 1586-91.
• 20 Chong AY, Blann AD, Patel J. et al. Endothelial dysfunction and damage in congestive heart failure. relation of flow-mediated dilation to circulating endothelial cells, plasma indexes of endothelial damage, and brain natriuretic peptide. Circulation 2004; 110: 1794-8.
• 21 Thompson SG, Kienast J, Pyke SDM, Haverkate F. et al. Haemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. New Engl J Med 1995; 332: 635-41.
• 22 Roldan V, Marin F, Lip G Y. et al. Soluble E-selectin in cardiovascular disease and its risk factors. A review of the literature. Thromb Haemost 2003; 90: 1007-20.
• 23 Preston RA, Ledford M, Materson B J. et al. Effects of severe, uncontrolled hypertension on endothelial activation: soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1 and von Willebrand factor. J Hypertens 2002; 20: 871-7.
• 24 Bitsch A, Klene W, Murtada L. et al. A longitudinal prospective study of soluble adhesion molecules in acute stroke. Stroke 1998; 29: 2129-35.
• 25 Fassbender K, Mossner R, Motsch L. et al. Circulating selectin- and immunoglobulin-type adhesion molecules in acute ischemic stroke. Stroke 1995; 26: 1361-4.
• 26 Pop GA, Koudstaal PJ, Meeder H J. et al. Predictive value of clinical history and electrocardiogram in pa-tients with transient ischemic attack or minor ischemic stroke for subsequent cardiac and cerebral ischemic events. The Dutch TIA Trial Study Group. Arch Neurol 1994; 51: 333-41.
• 27 Gates P, Peppard R, Kempster P. et al. Clinically unsuspected cardiac disease in patients with cerebral ischaemia. Clin Exp Neurol 1987; 23: 75-80.
• 28 Pigott R, Dillon LP, Hemingway I H. et al. Soluble forms of Eselectin, ICAM1 and VCAM1 are present in the supernatants of cytokine activated cultured endothelial cells. Biochem Biophys Res Comm 1992; 187: 5849.
• 29 Burger PE, Coetzee S, McKeehan WL. et al. Fibroblast growth factor receptor-1 is expressed by endothelial progenitor cells. Blood 2002; 100: 3527-35.
• 30 Trojan L, Thomas D, Friedrich D. et al. Expression of different vascular endothelial markers in prostate cancer and BPH tissue: an immunohistochemical and clinical evaluation. Anticancer Res 2004; 24: 1651-6.
• 31 Lackner C, Jukic Z, Tsybrovskyy O. et al. Prognostic relevance of tumour-associated macrophages and von Willebrand factor-positive microvessels in colorectal cancer. Virchows Arch 2004; 445: 160-7.
• 32 De Raeve H, Van Marck E, Van Camp B. et al. Angiogenesis and the role of bone marrow endothelial cells in haematological malignancies. Histol Histopathol 2004; 19: 935-50.
• 33 George F, Brisson C, Poncelet P. et al. Rapid isolation of human endothelial cells from whole blood using S-Endo-1 monoclonal antibody coupled to immuno-magnetic beads: demonstration of endothelial injury after angioplasty. Thromb Haemost 1992; 67: 147-53.
• 34 Blann AD, Woywodt A, Bertolini F. et al. Circulating endothelial cells: Biomarker of vascular disease. Thromb Haemost 2005; 93: 228-35.
• 35 McClung JA, Naseer N, Saleem M. et al. Circulating endothelial cells are elevated in patients with type 2 diabetes mellitus independently of HbA(1)c. Diabetologia 2005; 48: 345-50.
• 36 Solovey A, Gui L, Key N S. et al. Tissue factor expression by endothelial cells in sickle cell anaemia. J Clin Invest 1998; 101: 1899-904.
• 37 Wagner DD. Cell biology of von Willebrand factor. Ann Rev Cell Biol 1990; 6: 217-46.