On the influence of glycocalyx on NO biosynthesis: The role of sulodexide
https://doi.org/10.21518/ms2025-008
Abstract
The glycocalyx is a special ultra-fine structure of glycosaminoand proteoglycans, 0.2–5 μm thick, covering the endothelium. Maintenance of the mechanisms of synthesis and secretion of the signaling molecule NO, this regulator of vascular tone, mitochondrial respiration, neurotransmission and immunity, occurs through the reconstruction of the glycocalyx. Sulodexide is a combination of natural glycosaminoglycans – heparan sulfate and dermatan sulfate, which are part of the glycocalyx. The antithrombotic effect of sulodexide, realized through the suppression of platelet adhesion and aggregation, mild anticoagulant and profibrinolytic effects, is well known. In addition to the prevention of thrombus formation, the use of sulodexide is one of the important areas of endothelial dysfunction therapy through the restoration of glycocalyx and NO biosynthesis. Evidence shows that the use of sulodexide is promising for the treatment of both arterial and venous thrombotic disorders in patients with type 2 diabetes mellitus (T2DM), arterial hypertension (AH), coronavirus infection COVID-19, after surgery, with thrombophilia, etc. A meta-analysis of study data demonstrates a reduced risk of death from cardiovascular causes with the use of sulodexide. As part of the personalized prescription of sulodexide, the results of endothelial dysfunction diagnostics should be taken into account. If the patient has a risk of thrombotic events, anticoagulants and antiplatelet agents should be used in accordance with clinical guidelines. Sulodexide has antithrombotic properties and is characterized by a low level of bleeding; it should be used when it is impossible to use anticoagulants with a high risk of bleeding, as well as if the patient has hypertension, type 2 diabetes, chronic venous diseases, and diseases of the arteries of the lower extremities.
About the Authors
O. A. GromovaRussian Federation
Olga A. Gromova, Dr. Sci. (Med.), Professor, Leading Researcher
44, Bldg. 2, Vavilov St., Moscow, 119333
I. Yu. Torshin
Russian Federation
Ivan Yu. Torshin, Cand. Sci. (Phys.-Math.), Cand. Sci. (Chem.), Leading Researcher
44, Bldg. 2, Vavilov St., Moscow, 119333
A. G. Chuchalin
Russian Federation
Alexander G. Chuchalin, Acad. RAS, Dr. Sci. (Med.), Professor, Head of the Department of Hospital Therapy, Faculty of Pediatrics
1, Ostrovityanov St., Moscow, 117997
References
1. Böhm EW, Buonfiglio F, Korb CA, Dauth A, Pfeiffer N, Bręborowicz A, Gericke A. Potential of Sulodexide in the Treatment of Diabetic Retinopathy and Retinal Vein Occlusion. Thromb Haemost. 2025;125(04):291–307. https://doi.org/10.1055/s-0044-1791232.
2. Wang T, Xu J, Sun Y, Liu L, Li Y, Cai X, Chen M, Fang Y. Efficacy of sulodexide in treating idiopathic membranous nephropathy among Chinese patients: a meta-analysis. Am J Transl Res. 2024;16(7):2756–2764. https://doi.org/10.62347/RNLQ2888.
3. Zieliński A, Jasińska-Sumińska K, Bręborowicz A, Kowalska K, Zabel M, Wysocka T et al. Changes of the serum properties and its effect on the endothelial cells restoration in patients with chronic venous disease treated with sulodexide. J Vasc Surg Venous Lymphat Disord. 2024;12(5):101941. https://doi.org/10.1016/j.jvsv.2024.101941.
4. Bikdeli B, Chatterjee S, Kirtane AJ, Parikh SA, Andreozzi GM, Desai NR et al. Sulodexide versus Control and the Risk of Thrombotic and Hemorrhagic Events: Meta-Analysis of Randomized Trials. Semin Thromb Hemost. 2020;46(8):908–918. https://doi.org/10.1055/s-0040-1716874.
5. Mauro M, Palmieri GC, Palazzini E, Barbanti M, Calanni Rindina F, Milani MR. Pharmacodynamic effects of single and repeated doses of oral sulodexide in healthy volunteers. A placebo-controlled study with an enteric-coated formulation. Curr Med Res Opin. 1993;13(2):87–95. https://doi.org/10.1185/03007999309111537.
6. Pompilio G, Integlia D, Raffetto J, Palareti G. Comparative Efficacy and Safety of Sulodexide and Other Extended Anticoagulation Treatments for Prevention of Recurrent Venous Thromboembolism: A Bayesian Network Meta-analysis. TH Open. 2020;4(2):e80-e93. https://doi.org/10.1055/s-0040-1709731.
7. Ors Yildirim N, Yildirim AK, Demeli Ertus M, Dastan AO, Pehlivanoglu B, Chi YW et al. Sulodexide Inhibits Arterial Contraction via the EndotheliumDependent Nitric Oxide Pathway. J Clin Med. 2024;13(8):2332. https://doi.org/10.3390/jcm13082332.
8. Federici M, Menghini R, Mauriello A, Hribal ML, Ferrelli F, Lauro D et al. Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells. Circulation. 2002;106(4):466–472. https://doi.org/10.1161/01.cir.0000023043.02648.51.
9. Schlichting D, McCollam JS. Recognizing and managing severe sepsis: a common and deadly threat. South Med J. 2007;100(6):594–600. https://doi.org/10.1097/SMJ.0b013e31804aa29f.
10. Cyr AR, Huckaby LV, Shiva SS, Zuckerbraun BS. Nitric Oxide and Endothelial Dysfunction. Crit Care Clin. 2020;36(2):307–321. https://doi.org/10.1016/j.ccc.2019.12.009.
11. Bahadoran Z, Mirmiran P, Ghasemi A. Adipose organ dysfunction and type 2 diabetes: Role of nitric oxide. Biochem Pharmacol. 2024;221:116043. https://doi.org/10.1016/j.bcp.2024.116043.
12. Clancy RM, Amin AR, Abramson SB. The role of nitric oxide in inflammation and immunity. Arthritis Rheum. 1998;41(7):1141–1151. https://doi.org/10.1002/1529-0131(199807)41:73.0.CO;2-S.
13. Torshin IYu, Gromova OA, Chuchalin AG, Mayorova LA. Vitamins and other nutrients that support nitric oxide homeostasis and counteract the development of endotheliopathy. Neurology, Neuropsychiatry, Psychosomatics. 2024;16(6):89–96. (In Russ.) https://doi.org/10.14412/2074-2711-2024-6-89-96.
14. Bai J, Wang Q, Qi J, Yu H, Wang C, Wang X et al. Promoting effect of baicalin on nitric oxide production in CMECs via activating the PI3K-AKT-eNOS pathway attenuates myocardial ischemia-reperfusion injury. Phytomedicine. 2019;63:153035. https://doi.org/10.1016/j.phymed.2019.153035.
15. Gwozdzinski L, Bernasinska-Slomczewska J, Hikisz P, Wiktorowska-Owczarek A, Kowalczyk E, Pieniazek A. The Effect of Diosmin, Escin, and Bromelain on Human Endothelial Cells Derived from the Umbilical Vein and the Varicose Vein-A Preliminary Study. Biomedicines. 2023;11(6):1702. https://doi.org/10.3390/biomedicines11061702.
16. Gao G, Nakamura S, Asaba S, Miyata Y, Nakayama H, Matsui T. Hesperidin Preferentially Stimulates Transient Receptor Potential Vanilloid 1, Leading to NO Production and Mas Receptor Expression in Human Umbilical Vein Endothelial Cells. J Agric Food Chem. 2022;70(36):11290–11300. https://doi.org/10.1021/acs.jafc.2c04045.
17. Dobiaš L, Petrová M, Vojtko R, Kristová V. Long-term Treatment with Hesperidin Improves Endothelium-dependent Vasodilation in Femoral Artery of Spontaneously Hypertensive Rats: The Involvement of NO-synthase and K(v) Channels. Phytother Res. 2016;30(10):1665–1671. https://doi.org/10.1002/ptr.5670.
18. Voronkov AV, Tiurenkov IN. Effect of cardiovascular drugs on vasodilating endothelial function in animals with experimental deficiency of sex hormones. Eksperimentalnaya i Klinicheskaya Farmakologiya. 2011;74(10):23–25. (In Russ.) Available at: https://pubmed.ncbi.nlm.nih.gov/22238982.
19. Masola V, Zaza G, Onisto M, Lupo A, Gambaro G. Glycosaminoglycans, proteoglycans and sulodexide and the endothelium: biological roles and pharmacological effects. Int Angiol. 2014;33(3):243–254. Available at: https://pubmed.ncbi.nlm.nih.gov/24936533.
20. Zhao F, Zhong L, Luo Y. Endothelial glycocalyx as an important factor in composition of blood-brain barrier. CNS Neurosci Ther. 2021;27(1):26–35. https://doi.org/10.1111/cns.13560.
21. Shen Y, He Y, Pan Y, Liu L, Liu Y, Jia J. Role and mechanisms of autophagy, ferroptosis, and pyroptosis in sepsis-induced acute lung injury. Front Pharmacol. 2024;15:1415145. https://doi.org/10.3389/fphar.2024.1415145.
22. Song JW, Zullo J, Lipphardt M, Dragovich M, Zhang FX, Fu B, Goligorsky MS. Endothelial glycocalyx-the battleground for complications of sepsis and kidney injury. Nephrol Dial Transplant. 2018;33(2):203–211. https://doi.org/10.1093/ndt/gfx076.
23. Liu Y, Chen S, Liu S, Sun G, Sun Z, Liu H. Association of endothelial glycocalyx shedding and coronary microcirculation assessed by an angiographyderived index of microcirculatory resistance in patients with suspected coronary artery disease. Front Cardiovasc Med. 2022;9:950102. https://doi.org/10.3389/fcvm.2022.950102.
24. Hána L, Kočí J, Pohnán R, Řehák D, Astapenko D. The significance of glycocalyx in surgery. Rozhl Chir. 2023;102(12):453–458. https://doi.org/10.33699/PIS.2023.102.12.453-458.
25. Fei Y, Huang X, Ning F, Qian T, Cui J, Wang X, Huang X. NETs induce ferroptosis of endothelial cells in LPS-ALI through SDC-1/HS and downstream pathways. Biomed Pharmacother. 2024;175:116621. https://doi.org/10.1016/j.biopha.2024.116621.
26. Dörnyei G, Monos E, Kaley G, Koller A. Regular exercise enhances blood pressure lowering effect of acetylcholine by increased contribution of nitric oxide. Acta Physiol Hung. 2000;87(2):127–138. Available at: https://pubmed.ncbi.nlm.nih.gov/11205960.
27. Chen SJ, Wu CC, Yen MH. Exercise training activates large-conductance calcium-activated K(+) channels and enhances nitric oxide production in rat mesenteric artery and thoracic aorta. J Biomed Sci. 2001;8(3):248–255. https://doi.org/10.1007/BF02256598.
28. Majerczak J, Grandys M, Duda K, Zakrzewska A, Balcerczyk A, Kolodziejski L et al. Moderate-intensity endurance training improves endothelial glycocalyx layer integrity in healthy young men. Exp Physiol. 2017;102(1):70–85. https://doi.org/10.1113/EP085887.
29. Li T, Liu X, Zhao Z, Ni L, Liu C. Sulodexide recovers endothelial function through reconstructing glycocalyx in the balloon-injury rat carotid artery model. Oncotarget. 2017;8(53):91350–91361. https://doi.org/10.18632/oncotarget.20518.
30. Gabryel B, Jarząbek K, Machnik G, Adamczyk J, Belowski D, Obuchowicz E, Urbanek T. Superoxide dismutase 1 and glutathione peroxidase 1 are involved in the protective effect of sulodexide on vascular endothelial cells exposed to oxygen-glucose deprivation. Microvasc Res. 2016;103:26–35. https://doi.org/10.1016/j.mvr.2015.10.001.
31. Tiurenkov IN, Voronkov AV, Slietsans AA, Snigur GL. [Effects of mexidol and sulodexide on the level of specific markers of endothelial dysfunction in animals with experimental diabetes mellitus]. Eksp Klin Farmakol. 2012;75(5):14–16. Available at: https://pubmed.ncbi.nlm.nih.gov/22834122.
32. Li P, Ma LL, Xie RJ, Xie YS, Wei RB, Yin M et al. Treatment of 5/6 nephrectomy rats with sulodexide: a novel therapy for chronic renal failure. Acta Pharmacol Sin. 2012;33(5):644–651. https://doi.org/10.1038/aps.2012.2.
33. Broekhuizen LN, Lemkes BA, Mooij HL, Meuwese MC, Verberne H, Holleman F et al. Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus. Diabetologia. 2010;53(12):2646–2655. https://doi.org/10.1007/s00125-010-1910-x.
34. Olde Engberink RH, Rorije NM, Lambers Heerspink HJ, De Zeeuw D, van den Born BJ, Vogt L. The blood pressure lowering potential of sulodexide – a systematic review and meta-analysis. Br J Clin Pharmacol. 2015;80(6):1245–1253. https://doi.org/10.1111/bcp.12722.
35. Charfeddine S, Ibnhadjamor H, Jdidi J, Torjmen S, Kraiem S, Bahloul A et al. Sulodexide Significantly Improves Endothelial Dysfunction and Alleviates Chest Pain and Palpitations in Patients With Long-COVID-19: Insights From TUN-EndCOV Study. Front Cardiovasc Med. 2022;9:866113. https://doi.org/10.3389/fcvm.2022.866113.
36. Ćurko-Cofek B, Jenko M, TaleskaStupica G, Batičić L, Krsek A, Batinac T et al. The Crucial Triad: Endothelial Glycocalyx, Oxidative Stress, and Inflammation in Cardiac Surgery-Exploring the Molecular Connections. Int J Mol Sci. 2024;25(20):10891. https://doi.org/10.3390/ijms252010891.
37. Gaddi AV, Capello F, Gheorghe-Fronea OF, Fadda S, Darabont RO. Sulodexide improves pain-free walking distance in patients with lower extremity peripheral arterial disease: A systematic review and meta-analysis. JRSM Cardiovasc Dis. 2020;9:2048004020907002. https://doi.org/10.1177/2048004020907002.
38. Bignamini AA, Matuška J. Sulodexide for the Symptoms and Signs of Chronic Venous Disease: A Systematic Review and Meta-analysis. Adv Ther. 2020;37(3):1013–1033. https://doi.org/10.1007/s12325-020-01232-1.
39. Бурячковская ЛИ, Ломакин НВ, Сумароков АБ, Широков ЕА. Эффективность и безопасность антитромботической терапии. Шкалы и алгоритмы: клинические рекомендации. М.; 2018. Режим доступа: https://studfile.net/preview/21453749ю.
40. Ivanov AN, Grechikhin AA, Norkin IA, Puchinyan DM. Methods of endothelial dysfunction diagnosis. Regional Blood Circulation and Microcirculation. 2014;13(4):4–11. (In Russ.) Available at: https://www.microcirc.ru/jour/article/view/303.
Review
For citations:
Gromova OA, Torshin IY, Chuchalin AG. On the influence of glycocalyx on NO biosynthesis: The role of sulodexide. Meditsinskiy sovet = Medical Council. 2025;(5):196-205. (In Russ.) https://doi.org/10.21518/ms2025-008