Biopolym. Cell. 2020; 36(4):245-253.
Subendothelial matrix as the playground for “diabetic milieu” factors in development of angiopathy
1Nizheradze K. A., 2Khoruzhenko A. I.
  1. Bogomolets National Medical University
    13, Shevchenko Blvd., Kyiv, Ukraine, 01601
  2. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03143


Despite a few decades of intensive researches, the coherent view on the effector mechanisms causing development of diabetic angiopathy remains in demand. At the level of the whole organism, stable or intermittent hyperglycemia along with the altered levels of insulin, glycosylated proteins and lipoproteins, accompanied by modulation of intracellular metabolic pathways are considered as the main causative factors of diabetic micro- and macroangiopathy. At the tissue level, the general manifestation of vascular damage in diabetes appears as the basal membrane thickening. Here, based on the available literature and own experimental data, the changes in local microenvironment are considered as an important intermediate step in the realization of the effects of “diabetic milieu” factors on vessel wall cells. Special attention is paid to the carbohydrate determinants and deposition of von Willebrand factor in subendothelial matrix produced by endothelial cells in vitro.
Keywords: diabetic angiopathy, hyperglycemia, basal membrane, von Willebrand factor


[1] Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005; 54(6):1615-25.
[2] Flyvbjerg A. Diabetic angiopathy, the complement system and the tumor necrosis factor superfamily. Nat Rev Endocrinol. 2010;6(2):94-101.
[3] Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? Indian J Endocr Metab. 2016;20(4):546-53.
[4] Simon K, Wittmann I. Can blood glucose value really be referred to as a metabolic parameter? Rev Endocr Metab Disord. 2019;20(2):151-160.
[5] Kumar V, Cotran R, Robbins S. Basic pathology, 6th edition. Philadelphia: W.B. Saunders Company. 1997: 775 p.
[6] Kefalides N, Borel J (Eds). Basement membranes: cell and molecular biology. Academic Press. 2005; 428 p.
[7] Nizheradze K, Khoruzhenko A, Tronko N. Study in vitro of the effect of hyperglycemia and cell microenvironment on the von Willebrand factor content in subendothelial matrix. Dopov Nats Akad Nauk Ukr. 2005;(1): 175-83.
[8] Sprague RS, Ellsworth ML. Vascular disease in pre-diabetes: new insights derived from systems biology. Mo Med. 2010;107(4):265-9.
[9] Zhong Y, Yu S, Yu H, Yao J, Men L, Li Y, Wang Q, Du J. Selenoprotein S attenuates endothelial dysfunction in a diabetic vascular chip. Exp Gerontol. 2020; 137:110963, 1-12.
[10] Tsilibary E. Microvascular basement membranes in diabetes mellitus. J Pathol. 2003; 200(4): 537-546.
[11] Roy S, Ha J, Trudeau K, Beglova E. Vascular basement membrane thickening in diabetic retinopathy. Curr Eye Res. 2010;35(12):1045-56.
[12] Lieleg O, Baumgärtel RM, Bausch AR. Selective filtering of particles by the extracellular matrix: an electrostatic bandpass. Biophys J. 2009;97(6):1569-77.
[13] Tarallo S, Beltramo E, Berrone E, Dentelli P, Porta M. Effects of high glucose and thiamine on the balance between matrix metalloproteinases and their tissue inhibitors in vascular cells. Acta Diabetol. 2010;47(2):105-11.
[14] Fernig DG, Gallagher JT. Fibroblast growth factors and their receptors: an information network controlling tissue growth, morphogenesis and repair. Prog Growth Factor Res. 1994;5(4):353-77.
[15] Tzatsos A, Kandror KV. Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate1 phosphorylation. Mol Cell Biol. 2006;26(1):63-76.
[16] Nizheradze K, Tronko N. Use of culture of endothelial cells in studies of vascular pathology in diabetes mellitus. J NAMSU. 2003;9(4):713-35.
[17] Jaffe EA, Nachman RL, Becker CG, Minick CR. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest. 1973;52(11):2745-56.
[18] Nachman RL, Jaffe EA. Endothelial cell culture: beginnings of modern vascular biology. J Clin Invest. 2004;114(8):1037-40.
[19] Folkman J, Haudenschild CC, Zetter BR. Long-term culture of capillary endothelial cells. Proc Natl Acad Sci U S A. 1979;76(10):5217-21.
[20] Richard L, Velasco P, Detmar M. A simple immunomagnetic protocol for the selective isolation and long-term culture of human dermal microvascular endothelial cells. Exp Cell Res. 1998;240(1):1-6.
[21] 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.
[22] Wagner DD, Urban-Pickering M, Marder VJ. Von Willebrand protein binds to extracellular matrices independently of collagen. Proc Natl Acad Sci U S A. 1984;81(2):471-5.
[23] Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complications. 2001;15(1):44-54.
[24] Kessler L, Wiesel ML, Attali P, Mossard JM, Cazenave JP, Pinget M. Von Willebrand factor in diabetic angiopathy. Diabetes Metab. 1998;24(4):327-36.
[25] Kessler L, Azimzadeh A, Wiesel ML, Coumaros G, Chakfé N, Soyer C, Koehl C, Cazenave JP, Wolf P, Pinget M. Effect of insulin on von Willebrand factor release in normal and diabetic subjects: in vivo and in vitro studies. Horm Metab Res. 2001;33(11):674-80.
[26] Ascher E, Gade PV, Hingorani A, Puthukkeril S, Kallakuri S, Scheinman M, Jacob T. Thiamine reverses hyperglycemia-induced dysfunction in cultured endothelial cells. Surgery. 200;130(5):851-8.
[27] Li M, Qian M, Kyler K, Xu J. Endothelial-vascular smooth muscle cells interactions in atherosclerosis.Front Cardiovasc Med. 2018;5:151,1-8.
[28] de Groot PG, Reinders JH, Sixma JJ. Perturbation of human endothelial cells by thrombin or PMA changes the reactivity of their extracellular matrix towards platelets. J Cell Biol. 1987;104(3):697-704.
[29] Li J, Perrella MA, Tsai JC, Yet SF, Hsieh CM, Yoshizumi M, Patterson C, Endege WO, Zhou F, Lee ME. Induction of vascular endothelial growth factor gene expression by interleukin-1 beta in rat aortic smooth muscle cells. J Biol Chem. 1995;270(1):308-12.
[30] Rask-Madsen C, King GL. Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab. 2013;17(1):20-33.
[31] Martin A, Komada MR, Sane DC. Abnormal angiogenesis in diabetes mellitus. Med Res Rev. 2003;23(2):117-45.
[32] Nangia-Makker P, Baccarini S, Raz A. Carbohydrate-recognition and angiogenesis. Cancer Metastasis Rev. 2000;19(1-2):51-7.
[33] Markowska AI, Cao Z, Panjwani N. Glycobiology of ocular angiogenesis. Glycobiology. 2014;24(12):1275-82.
[34] Dogné S, Flamion B, Caron N. Endothelial glycocalyx as a shield against diabetic vascular complications: involvement of hyaluronan and hyaluronidases. Arterioscler Thromb Vasc Biol. 2018;38(7):1427-1439.
[35] Nieuwdorp M, van Haeften TW, Gouverneur MC, Mooij HL, van Lieshout MH, Levi M, Meijers JC, Holleman F, Hoekstra JB, Vink H, Kastelein JJ, Stroes ES. Loss of endothelial glycocalyx during acute hyperglycemia coin-cides with endothelial dysfunction and coagulation activation in vivo. Diabetes. 2006;55(2):480-6.
[36] Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: a review. Diabetologia. 2001;44(2):129-46.
[37] Nizheradze KA. Binding of wheat germ agglutinin to extracellular network produced by cultured human fibroblasts. Folia Histochem Cytobiol. 2000;38(4):167-73.
[38] Nizheradze K. Concanavalin A, but not glycated albumin, increases subendothelial deposition of von Willebrand factor in vitro. Endothelium. 2006;13(4):245-8.
[39] Hansen TK, Thiel S, Knudsen ST, Gravholt CH, Christiansen JS, Mogensen CE, Poulsen PL. Elevated levels of mannan-binding lectin in patients with type 1 diabetes. J Clin Endocrinol Metab. 2003;88(10):4857-61.
[40] Beltramo E, Buttiglieri S, Pomero F, Allione A, D'Alu F, Ponte E, Porta M. A study of capillary pericyte viability on extracellular matrix produced by endothelial cells in high glucose. Diabetologia. 2003;46(3):409-15.
[41] Beltramo E, Nizheradze K, Berrone E, Tarallo S, Porta M. Thiamine and benfotiamine prevent apoptosis induced by high glucose-conditioned extracellular matrix in human retinal pericytes. Diabetes Metab Res Rev. 2009;25(7):647-56.