Immunohistochemical and ultrasonic signs of the disturbance of anti-thrombogenic properties of endothelium in atherosclerosis of the carotid sinus

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Abstract

Introduction. Endothelial dysfunction is currently believed to play a crucial role in pathogenesis of atherosclerosis. Nevertheless, there are only few studies that demonstrate the relationship between changes in parameters of the atherosclerotic process and the main functional properties of endothelium. In addition, the findings are often controversial, which served as an incentive for this study.
Materials and methods. Thirteen atherosclerotic plaques resected during carotid endarterectomy were subjected to immunochemical and electron microscopy examination. The intensity of expression of the von Willebrand factor, thrombomodulin, and endothelial nitric acid synthase was assessed semi-quantitatively and compared to the main parameters of activity and the course of atherosclerosis in a plaque (volume of atheromatosis, lipophage aggregation, infiltration of the fibrous cap by monocytes and macrophages). Complicated and uncomplicated plaques were also compared.
Results. The level of von Willebrand factor in the carotid sinus endothelium increased as lipids were accumulated in it and as the fibrous cap was infiltrated by monocytes and macrophages (р<0.017), as opposed to the levels of thrombomodulin and endothelial nitric oxide synthase whose expression did not show the activity of the atherosclerotic process and did not correlate with the level of von Willebrand factor. Meanwhile, the expression of thrombomodulin and endothelial nitric oxide synthase correlated with each other (р=0.004). No difference in staining intensity for all three markers was detected between the complicated and uncomplicated plaques. Ultrasonic analysis of endothelium demonstrated the strongly pronounced disturbance of anti-thrombogenicity of the vascular wall as a result of numerous defects of the endothelial stratum, adhesion of blood cells to the arterial surface causing microthrombi formation and activation of endotheliocytes along with dystrophic changes in them, necrosis, and exfoliation into the vascular lumen.
Conclusions. The von Willebrand factor is found to have high diagnostic significance in the assessment of activity of the atherosclerotic process in the carotid sinus and the risk of developing complications. Thrombomodulin and endothelial nitric acid synthase are not recommended to be used as biomarkers of progression of atherosclerosis of this localization, since they are not indicative of the intensity of inflammatory response and destructive processes in a plaque.

About the authors

Anna N. Evdokimenko

Research Center of Neurology

Author for correspondence.
Email: evdokimenko@neurology.ru
Russian Federation, Moscow

Tatiana S. Gulevskaya

Research Center of Neurology

Email: evdokimenko@neurology.ru
Russian Federation, Moscow

Marine M. Tanashyan

Research Center of Neurology

Email: evdokimenko@neurology.ru
ORCID iD: 0000-0002-5883-8119

D. Sci. (Med.), Prof., Corresponding member of RAS, Deputy Director for science, Head, 1st Neurological department

Russian Federation, Moscow

References

  1. Becker B.F., Heindl B., Kupatt C., Zahler S. Endothelial function and hemostasis. Z Kardiol. 2000; 89(3): 160–167. PMID: 10798271
  2. Aird W.C. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res. 2007; 100(2): 158-173. doi: 10.1161/01.RES.0000255691.76142.4a. PMID: 17272818.
  3. Scherer D.J., Psaltis P.J. Future imaging of atherosclerosis: molecular imaging of coronary atherosclerosis with (18)F positron emission tomography. Cardiovasc Diagn Ther. 2016; 6(4): 354–367. doi: 10.21037/cdt.2015.12.02. PMID: 27500093.
  4. Falk E., Fernández-Ortiz A. Role of thrombosis in atherosclerosis and its complications. Am J Cardiol. 1995; 75(6): 3B-11B. PMID: 7863969.
  5. Broos K., Feys H.B., De Meyer S.F. et al. Platelets at work in primary hemostasis. Blood Rev. 2011; 25(4): 155–167. PMID: 21496978. doi: 10.1016/j.blre.2011.03.002.
  6. van Mourik J.A., Boertjes R., Huisveld I.A. et al. von Willebrand factor propeptide in vascular disorders: A tool to distinguish between acute and chronic endothelial cell perturbation. Blood 1999; 94(1): 179–185. PMID: 10381511.
  7. Blann A.D., McCollum C.N. von Willebrand factor, endothelial cell damage and atherosclerosis. Eur J Vasc Surg. 1994; 8(1): 10–15. PMID: 8307205.
  8. Theilmeier G., Michiels C., Spaepen E. et al. Endothelial von willebrand factor recruits platelets to atherosclerosis-prone sites in response to hypercholesterolemia. Blood 2002; 99 (12): 4486–4493. PMID: 12036879.
  9. McCarty O.J., Conley R.B., Shentu W. et al. Molecular imaging of activated von willebrand factor to detect high-risk atherosclerotic phenotype. JACC Cardiovasc Imaging 2010; 3 (9): 947–955. PMID: 20846630. doi: 10.1016/j.jcmg.2010.06.013.
  10. Reidy M.A., Chopek M., Chao S. et al. Injury induces increase of von Willebrand factor in rat endothelial cells. Am J Pathol. 1989; 134(4): 857–864. PMID: 2650559.
  11. Suslina Z.A., Tanashyan M.M., Domashenko M.A. et al. [Endothelial dysfunction in patients with ischemic stroke]. Annaly klinicheskoy i eksperimental’noy nevrologii. 2008; 2(1): 4–11.
  12. Whincup P.H., Danesh J., Walker M. et al. Von Willebrand factor and coronary heart disease. Prospective study and meta-analysis. Eur Heart J. 2002; 23(22): 1764–1770. PMID: 12419296.
  13. Nightingale T., Cutler D. The secretion of von Willebrand factor from endothelial cells; an increasingly complicated story. J Thromb Haemost. 2013; 11 Suppl 1: 192–201. doi: 10.1111/jth.12225. PMID: 23809123.
  14. Takano S., Kimura S., Ohdama S., Aoki N. Plasma thrombomodulin in health and diseases. Blood 1990; 76(10): 2024–2029. PMID: 2173634.
  15. Boffa M.C., Karochkine M., Bérard M. Plasma thrombomodulin as a marker of endothelium damage. Nouv Rev Fr Hematol. 1991; 33(6): 529–530. PMID: 1667951.
  16. Seigneur M., Dufourcq P., Conri C. et al. Plasma thrombomodulin – new approach of endothelial damage. Int Angiol. 1993; 12(4): 85–93. PMID: 8207313.
  17. Laszik Z.G., Zhou X.J., Ferrell G.L. et al. Down-Regulation of Endothelial Expression of Endothelial Cell Protein C Receptor and Thrombomodulin in Coronary Atherosclerosis. American Journal of Pathology 2001; 159 (3): 797–802. doi: 10.1016/S0002-9440(10)61753-1. PMID: 11549570.
  18. Evdokimenko A.N. [Ultrastructural changes of endothelium in unstable atherosclerotic plaques of carotid sinus]. Mezhdunarodnyy zhurnal prikladnykh i fundamental’nykh issledovaniy 2015; 11(5): 639–647.
  19. Pawlak K., Myśliwiec M., Pawlak D. Kynurenine pathway – a new link between endothelial dysfunction and carotid atherosclerosis in chronic kidney disease patients. Adv Med Sci. 2010; 55(2): 196–203. doi: 10.2478/v10039-010-0015-6. PMID: 20439183.
  20. Taylan A., Sari I., Kozaci D.L. et al. Evaluation of various endothelial biomarkers in ankylosing spondylitis. Clin Rheumatol. 2012; 31: 23–28. doi: 10.1007/s10067-011-1760-z. PMID: 21556780.
  21. Salomaa V., Matei C., Aleksic N. et al. Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis. Lancet. 1999; 353(9166):1729–1734. PMID: 10347984.
  22. Thorand B., Baumert J., Herder C. et al. Soluble thrombomodulin as a predictor of type 2 diabetes: results from the MONICA/KORA Augsburg case-cohort study, 1984–1998. Diabetologia 2007; 50(3): 545–548. doi: 10.1007/s00125-006-0568-x. PMID: 17195062.
  23. Wu K.K. Soluble thrombomodulin and coronary heart disease. Curr Opin Lipidol 2003; 14(4): 373–375. doi: 10.1097/01. mol.0000083766.66245.44. PMID: 12865735.
  24. Karakas M., Baumert J., Herder C. et al. Soluble thrombomodulin in coronary heart disease: lack of an association in the MONICA/KORA case-cohort study. J Thromb Haemost. 2011; 9(5): 1078–1080.doi: 10.1111/j.1538–7836.2011.04229.x. PMID: 21320279.
  25. Dósa E., Szabó A., Prohászka Z. et al. Changes in the plasma concentration of soluble thrombomodulin in patients with severe carotid artery stenosis after eversion endarterectomy. Inflamm Res. 2005; 54(7): 289–294. doi: 10.1007/s00011-005-1354-9. PMID: 16134058.
  26. Ignarro L.J., Cirino G., Casini A., Napoli C. Nitric oxide as a signaling molecule in the vascular system: an overview. J Cardiovasc Pharmacol. 1999; 34(6): 879-886. PMID: 10598133.
  27. Tanashyan M. M., Raskurazhev A. A., Shabalina A. A. et al. [Biomarkers of cerebral atherosclerosis: the capabilities of early diagnosis and prognosis of individual risk]. Annaly klinicheskoy i eksperimental’noy nevrologii 2015; 9(3): 20–25.
  28. Förstermann U., Sessa W.C. Nitric oxide synthases: regulation and function. Eur Heart J. 2012; 33(7): 829–837. doi: 10.1093/eurheartj/ehr304. PMID: 21890489.
  29. Li H, Förstermann U. Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease. Curr Opin Pharmacol. 2013; 13(2): 161–167. doi: 10.1016/j.coph.2013.01.006. PMID: 23395155.

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Copyright (c) 2016 Evdokimenko A.N., Gulevskaya T.S., Tanashyan M.M.

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