M.G. Konopleva1, N.V. Korotkova2, R.E. Kalinin3, I.A. Suchkov4, L.V. Nikiforova5, N.Dzh. Mzhavanadze6

1–6 Ryazan State Medical University (Ryazan, Russia)

1 mari.konopleva.97@mail.ru, 2 fnv8@yandex.ru, 3 kalinin-re@yandex.ru, 4 i.suchkov@rzgmu.ru, 5 laris-nikiforova@yandex.ru, 6 nina_mzhavanadze@mail.ru

Varicose veins of the lower extremities is a socio-economic problem of modern society. There is still a lack of information on the pathophysiology of veins. In the publications of many authors there are data indicating the participation of the biochemical indicator transforming growth factor-β1 (TGF-β1) in the pathogenesis of varicose veins. Biochemical processes occurring in the wall of varicose veins require more detailed study. The aim of this work is to evaluate the concentration of transforming growth factor-β1 (TGF-β1) in the homogenate of the vascular wall in patients with varicose veins of the lower extremities depending on the stage of the disease according to the CEAP classification. The object of the study were patients with varicose veins of the lower extremities, the material for the study was the homogenate of the vascular wall. Biological material was collected from donors of the experimental group during phlebectomy for varicose veins. In patients of the control group, sections of healthy veins were taken during femoral-popliteal bypass surgery using autovena. The concentration of TGF-β1 was determined by the sandwich ELISA method in vascular wall homogenate using a Stat Fax 2100 enzyme immunoassay analyzer (microplate reader) (Awareness technology Inc. Palm City, FL 34990, USA). The results were expressed in pg/ml. The study revealed a statistically significant increase in the concentration of TGF-β1 by 1.4 times (p = 0.01) in the homogenate of the vascular wall of varicose veins compared to the control group; a tendency towards an increase in the level of TGF-β1 by 1.26 times (р = 0.049) in the homogenate of varicose veins with stage C2s disease compared to donors; Also, statistically significant increase in TGF-β1 concentration was noted at stages C3s and C4s by 2 (p = 0.0002) and 1.5 times (p = 0.036), respectively, compared to the control. Changes in the concentration of TGF-β1 may indicate a violation of its regulation and may be a central pathogenetic link in varicose veins of the lower extremities. Varicose veins of the lower extremities are associated with an increase in the level of TGF-β1 in vascular wall homogenates compared with healthy donors, which may be a marker of this pathology. Further research is needed to find out how the regulation of TGF-β1 is disrupted, which leads to varicose veins of the lower extremities.

1. Shanaev I.N., Korbut V.S., Hashumov R.M. Atipichnye formy varikoznoj bolezni ven nizhnih konechnostej: osobennosti diagnostiki i operativnogo lecheniya. Rossijskij mediko-biologicheskij vestnik im. akademika I.P. Pavlova. 2023. T. 31(4). S. 551–562. DOI: 10.17816/PAVLOVJ107079 (in Russian).
2. Kalinin R.E., Suchkov I.A., Shanaev I.N., Yudin V.A. Gemodinamicheskie narusheniya pri varikoznoj bolezni. Nauka molo-dyh (Eruditio Juvenium). 2021. T. 9(1). S. 68–76. DOI: 10.23888/HMJ20219168-76 (in Russian).
3. Tihonova G.A., Kotov O.V., Markin A.A. Biomarkery kak instrumenty mediko-biologicheskogo monitoringa i kontrolya (Ob-zor literatury. CHast' 2). Tekhnologii zhivyh sistem. 2023. T. 20. № 4. S. 5–18. DOI: 10.18127/j20700997-202304-01 (in Russian).
4. Birdina J., Pilmane M., Ligers A. The Morphofunctional Changes in the Wall of Varicose Veins. Ann. Vasc. Surg. 2017. V. 42. P. 274–284. DOI: 10.1016/j.avsg.2016.10.064
5. Oklu R., Habito R., Mayr M. et al. Pathogenesis of varicose veins. J. Vasc. Interv. Radiol. 2012. V. 23(1). P. 33–39. DOI: 10.1016/j.jvir.2011.09.010
6. Kim K.K., Sheppard D., Chapman H.A. TGF-β1 Signaling and Tissue Fibrosis. Cold Spring Harb. Perspect. Biol. 2018. V. 10(4). P. 2022293. DOI: 10.1101/cshperspect.a022293
7. Lambers C., Roth M., Zhong J. et al. The interaction of endothelin-1 and TGF-β1 mediates vascular cell remodeling. PLoS One. 2013. V. 8(8). P. e73399. DOI: 10.1371/journal.pone.0073399
8. Kamaev A.A., Bulatov V.L., Vahrat'yan P.E. i dr. Varikoznoe rasshirenie ven. Flebologiya. 2022. T. 16(1). S. 41–108. DOI: 10.17116/flebo20221601141 (in Russian).
9. Kubichkova L., Sedlarikova L., Hajek R. TGF-β – otlichnyj sluga, no plohoj hozyain. J. Transl. Med. 2012. T. 10. S. 183. DOI: 10.1186/1479-5876-10-183 (in Russian).
10. Golovina V.I., Seliverstov E.I., Efremova O.I., Zolotuhin I.A. Rol' citokinov v patogeneze varikoznoj bolezni. Fle-bologiya. 2021. T. 15(2). S. 117–126. DOI: 10.17116/flebo202115021117 (in Russian).
11. Shevchenko O.P., Kurabekova R.M., Cirul'nikova O.M. Rol' transformiruyushchego faktora rosta beta-1 pri zabolevaniyah pecheni. Klinicheskaya laboratornaya diagnostika. 2017. T. 62(3). S. 161–164. DOI: 10.18821/0869-2084-2017-62-3-161-164 (in Russian).
12. Baik J.E., Park H.J., Kataru R.P. et al. TGF-β1 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation. Clin. Transl. Med. 2022. V. 12(6). P. e758. DOI: 10.1002/ctm2.758
13. Serralheiro P., Soares A., Costa Almeida C.M., Verde I. TGF-β1 in vascular wall pathology: Unraveling chronic venous insufficiency pathophysiology. Int. J. Mol. Sci. 2017. V. 18(12). P. 2534. DOI: 10.3390/ijms18122534
14. Kalinin R.E., Konoplyova M.G., Suchkov I.A. i dr. Interlejkin-13: svyaz' s vospaleniem i cisteinovym proteolizom pri va-rikoznoj transformacii sosudistoj stenki. Kazanskij medicinskij zhurnal. 2023. T. 104(6). S. 896–906. DOI: 10.17816/KMJ430382 (in Russian).
15. Kowalewski R., Malkowski A., Sobolewski K., Gacko M. Evaluation of transforming growth factor-beta signaling pathway in the wall of normal and varicose veins. Pathobiology. 2010. V. 77(1). P. 1–6. DOI: 10.1159/000272948
16. Yariev A.A., Hudojberdiev S.S., Boboev K.T. i dr. Svyaz' polimorfizmov genov TGF-β1 i MTHFR c razvitiem varikoznoj bolezni i eyo tromboticheskih oslozhnenij. Vestnik ekstrennoj mediciny. 2022. T. 15(5). S. 38–41. DOI: 10.54185/TBEM/vol15_iss5/a5 (in Russian).
17. Redondo S., Navarro-Dorado J., Ramajo M. Age-dependent defective TGF-beta1 signaling in patients undergoing coronary artery bypass grafting. J. Cardiothorac. Surg. 2014. DOI: 10.1186/1749-8090-9-24
18. Chen C., Lei W., Chen W. et al. Serum TGF-β1 and SMAD3 levels are closely associated with coronary artery disease. BMC Cardiovasc. Disord. 2014. V. 14 (18). P. 14–18. DOI: 10.1186/1471-2261-14-18
19. Ridwan M., Dimiati H., Syukri M. et al. Potential molecular mechanism underlying cardiac fibrosis in diabetes mellitus: a narrative review. Egypt Heart. 2023. V. 75. P. 46. DOI: 10.1186/s43044-023-00376-z
20. Musil D. What's new in the 2020 update of the CEAP classification system of chronic venous disease? Vnitr. Lek. 2021. V. 67(3). P. 143–148.
21. Luk'yanova YU.S., Pokrovskij M.V. Osnovnye patofiziologicheskie i molekulyarnye mekhanizmy hronicheskih zabolevanij ven i ih farmakologicheskaya korrekciya. Klinicheskaya farmakologiya i terapiya. 2019. T. 28(3). S. 52–61. (in Russian).
22. Meng X.M., Nikolic-Paterson D.J., Lan H.Y. TGF-β: the master regulator of fibrosis. Nat. Rev. Nephrol. 2016. V. 12(6). P. 325–338. DOI: 10.1038/nrneph.2016.48
23. Kurabekova R.M., SHevchenko O.P., Cirul'nikova O.M. Transformiruyushchij faktor rosta-β1 pri transplantacii pecheni. Vestnik transplantologii i iskusstvennyh organov. 2015. T. 17(3). S. 76–82. DOI: 10.15825/1995-1191-2015-3-76-82 (in Russian).
24. Kolosova I., Nethery D., Kern J.A. Role of Smad2/3 and p38 MAP kinase in TGF-β1-induced epithelial-mesenchymal transition of pulmonary epithelial cells. J. Cell Physiol. 2011. V. 226(5). P. 1248–1254. DOI: 10.1002/jcp.22448
25. Shurygina I.A., Shurygin M.G., Zelenin N.V., Granina G.B. Rol' MAR-kinaznyh mekhanizmov v regulyacii kletochnogo rosta. Sibirskij medicinskij zhurnal. 2009. T. 89(6). S. 36–40. (in Russian).
26. Shurygina I.A., Shurygin M.G., Zelenin N.V., Ayushinova N.I. Vozdejstvie na mitogenaktiviruemye proteinkinazy kak novoe napravlenie regulyacii rosta soedinitel'noj tkani. Byulleten' sibirskoj mediciny. 2017. T. 16(4). S. 86–93. DOI: 10.20538/1682-0363-2017-4-86–93 (in Russian).
27. Hu H.H., Chen D.Q., Wang Y.N. et al. New insights into TGF-β/Smad signaling in tissue fibrosis. Chem. Biol. Interact. 2018. V. 292. P. 76–83. DOI: 10.1016/j.cbi.2018.07.008