T cells as regulators of angiogenesis (a literature review)
https://doi.org/10.15825/1995-1191-2026-2-94-103
Abstract
T cells not only provide cellular immunity, but also exert control over the proliferation, differentiation, and maturation of cells across diverse target tissues, thereby regulating both physiological and reparative regenerative processes. Evidence demonstrates that these cells contribute to the restoration of parenchymal organ structures, promote osteogenic differentiation of mesenchymal stem cells, activate neurogenesis, and modulate myogenesis and angiogenesis. This review focuses on the mechanisms by which T cells regulate reparative processes within the vascular system, highlighting key aspects such as cell–cell interactions between T cells and endothelial cells, the role of chemokine receptors in mediating T-cell adhesion to the endothelium, and their capacity to synthesize angiogenic growth factors including interferon-γ (IFN-γ), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), tumor necrosis factor-α (TNF-α), insulin-like growth factor-1 (IGF-1), amphiregulin, and a broad range of interleukins. The review also describes the ability of T cells to control post-transcriptional regulation of gene expression in endothelial cells through small non-coding RNA molecules (miRNAs). Specifically, information is provided on the angiogenic roles of miRNAs previously identified in T cells: miR-16, miR-21, miR-25, miR-150, miR-155, miR-181, and miR-451, and the mechanisms through which they mediate these effects.
About the Author
N. V. Tishevskaya
South Ural State Medical University
Russian Federation
Russian Federation
Natalya V. Tishevskaya.
64, Vorovskogo str., Chelyabinsk, 454092
Phone: (351) 232-74-67
References
1. Evans CE, Iruela‑Arispe ML, Zhao YY. Mechanisms of endothelial regeneration and vascular repair and their application to regenerative medicine. Am J Pathol. 2021; 191 (1): 52–65. doi: 10.1016/j.ajpath.2020.10.001.
2. Babaeva AG, Gevorkyan NM, Zotikov EA. Rol’ limfocitov v operativnom izmenenii programmy razvitiâ tkanej. M.: RAMN, 2009; 108. [In Russ].
3. D’Alessio FR, Kurzhagen JT, Rabb H. Reparative T lymphocytes in organ injury. J Clin Invest. 2019; 129: 2608–2618. doi: 10.1172/JCI124614.
4. Grassi F, Cattini L, Gambari L, Manferdini C, Piacentini A, Gabusi E et al. T cell subsets differently regulate osteogenic differentiation of human mesenchymal stromal cells in vitro. J Tissue Eng Regen Med. 2013; 10 (4): 305–314. doi: 10.1002/term.1727.
5. Liu J, Ma Y, Tian S, Zhang L, Zhao M, Zhang Y, Xu D. T cells promote the regeneration of neural precursor cells in the hippocampus of Alzheimer’s disease mice. Neural Regen Res. 2014; 9 (16): 1541–1547. doi: 10.4103/1673-5374.139481.
6. Kwee BJ, Budina E, Najibi AJ, Mooney DJ. CD4 T-cells regulate angiogenesis and myogenesis. Biomaterials. 2018; 178: 109–121. doi: 10.1016/j.biomaterials.2018.06.003.
7. Alcaide P. Mechanisms Regulating T cell-endothelial cell interactions. Cold Spring Harb Perspect Med. 2022; 12 (7): a041170. doi: 10.1101/cshperspect.a041170.
8. Vdovenko D, Balbi C, Di Silvestre D, Passignani G, Puspitasari YM, Zarak‑Crnkovic M et al. Microvesicles released from activated CD4(+) T cells alter microvascular endothelial cell function. Eur J Clin Invest. 2022; 52 (6): e13769. doi: 10.1111/eci.13769.
9. Tamosiuniene R, Tian W, Dhillon G, Wang L, Sung YK, Gera L et al. Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ Res. 2011; 109 (8): 867–879. doi: 10.1161/CIR-CRESAHA.110.236927.
10. Buckley DJ, Sharma S, Joseph B, Fayyaz AH, Canizales A, Terrebonne KJ, Trott DW. Early life thymectomy induces arterial dysfunction in mice. Geroscience. 2024; 46 (1): 1035–1051.
11. Deliyanti D, Figgett WA, Gebhardt T, Trapani JA, Mackay F, Wilkinson‑Berka JL. CD8(+) T cells promote pathological angiogenesis in ocular neovascular disease. Arterioscler Thromb Vasc Biol. 2023; 43 (4): 522–536. doi: 10.1161/ATVBAHA.122.318079.
12. Do Valle Duraes F, Lafont A, Beibel M, Martin K, Darribat K, Cuttat R et al. Immune cell landscaping reveals a protective role for regulatory T cells during kidney injury and fibrosis. JCI Insight. 2020; 5 (3): e130651. doi: 10.1172/jci.insight.130651.
13. Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, Sitkovsky MV. Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol. 2001; 167 (11): 6140–6149. doi: 10.4049/jimmunol.167.11.6140.
14. Lin Y, Tang Y, Wang F. The Protective effect of HIF-1α in T lymphocytes on cardiac damage in diabetic mice. Ann Clin Lab Sci. 2016; 46 (1): 32–43.
15. Yun H, Yee MB, Lathrop KL, Kinchington PR, Hendricks RL, St Leger AJ. Production of the cytokine VEGF-A by CD4(+) T and myeloid cells disrupts the corneal nerve landscape and promotes herpes stromal keratitis. Immunity. 2020; 53 (5): 1050–1062.e5. doi: 10.1016/j.immuni.2020.10.013.
16. Schilbach K, Frommer K, Meier S, Handgretinger R, Eyrich M. Immune response of human propagated gammadelta‐T cells to neuroblastoma recommend the Vdelta1+ subset for gammadelta‐T cell‐based immunotherapy. J Immunother. 2008; 31: 896–905. doi: 10.1097/CJI.0b013e31818955ad.
17. Certo M, Elkafrawy H, Pucino V, Cucchi D, Cheung KCP, Mauro C. Endothelial cell and T-cell crosstalk: Targeting metabolism as a therapeutic approach in chronic inflammation. Br J Pharmacol. 2021; 178 (10): 2041–2059. doi: 10.1111/bph.15002.
18. Jung J, Zeng H, Horng T. Metabolism as a guiding force for immunity. Nature Cell Biology. 2019; 21 (1): 85–93. doi: 10.1038/s41556-018-0217-x.
19. Loffredo LF, Savage TM, Ringham OR, Arpaia N. Treg-tissue cell interactions in repair and regeneration. J Exp Med. 2024; 221 (6): e20231244. doi: 10.1084/jem.20231244.
20. Qi Y, Operario DJ, Georas SN, Mosmann TR. The acute environment, rather than T cell subset pre-commitment, regulates expression of the human T cell cytokine amphiregulin. PLoS One. 2012; 7 (6): e39072. doi: 10.1371/journal.pone.0039072.
21. Liu J, Pan L, Hong W, Chen S, Bai P, Luo W et al. GPR174 knockdown enhances blood flow recovery in hindlimb ischemia mice model by upregulating AREG expression. Nat Commun. 2022; 13: 7519. doi: 10.1038/s41467-022-35159-8.
22. Leung OM, Li J, Li X, Chan VW, Yang KY, Ku M et al. Regulatory T cells promote apelin-mediated sprouting angiogenesis in type 2 diabetes. Cell Rep. 2018; 24: 1610–1626. doi: 10.1016/j.celrep.2018.07.019.
23. Wang Y, Li J, Zhang Y, He P, Liu W, Zeng W et al. AREG(+) regulatory T cells mediating myocardial repair and neovascularization after myocardial infarction. Mol Med. 2025; 31 (1): 229. doi: 10.1186/s10020-025-01281-8.
24. Gevorkyan NM, Tishevskaya NV, Bolotov AA. Effect of preliminary administration of total RNA of bone marrow cells on the dynamics of erythropoiesis recovery in rats after acute gamma irradiation. Byulleten’ eksperimental’noy biologii i meditsiny. 2016; 161 (5): 670–673. doi: 10.1007/s10517-016-3494-z. [In Russ. English abstract].
25. Babaeva AG, Gevorkyan NM, Tishevskaya NV, Komarova IA. Effects of preparations of total RNA from lymphoid cells of rat spleen on in vitro erythropoiesis. Klinicheskaya i eksperimental’naya morfologiya. 2014; 4 (12): 35–39. [In Russ].
26. Babaeva AG, Gevorkyan NM, Tishevskaya NV, Komarova IA. Influence of preparations of total RNA from splenic lymphoid cells on erythropoiesis in the culture of erythroblastic islets from rats with polycythemia. Klinicheskaya i eksperimental’naya morfologiya. 2014; 4 (12): 40–43. [In Russ].
27. Tishevskaya NV, Golovneva ES, Takhaviev RV. Lymphocytic RNA stimulates physiological regeneration and enhances microcirculation in the thyroid gland. Russian Journal of Transplantology and Artificial Organs. 2025; 27 (2): 163–170. doi: 10.15825/1995-1191-2025-2-163-170.
28. Shang R, Lee S, Senavirathne G, Lai EC. MicroRNAs in action: biogenesis, function and regulation. Nat Rev Genet. 2023; 24 (12): 816–833. doi: 10.1038/s41576-023-00611-y.
29. Ding M‑H, Lozoya EG, Rico RN, Chew SA. The role of angiogenesis-inducing microRNAs in vascular tissue engineering. Tissue Eng Part A. 2020; 26 (23–24): 1283–1302.
30. Kuchen S, Resch W, Yamane A, Kuo N, Li Z, Chakraborty T et al. Regulation of microRNA expression and abundance during lymphopoiesis. Immunity. 2010; 32 (6): 828–839. doi: 10.1016/j.immuni.2010.05.009.
31. Grigoryev YA, Kurian SM, Hart T, Nakorchevsky AA, Chen C, Campbell D et al. MicroRNA regulation of molecular networks mapped by global microRNA, mRNA, and protein expression in activated T lymphocytes. J Immunol. 2011; 187 (5): 2233–2243. doi: 10.4049/jimmunol.1101233.
32. Smigielska‑Czepiel K, van den Berg A, Jellema P, van der Lei RJ, Bijzet J, Kluiver J et al. Comprehensive analysis of miRNA expression in T-cell subsets of rheumatoid arthritis patients reveals defined signatures of naive and memory Tregs. Genes Immun. 2014; 15 (2): 115–125. doi: 10.1038/gene.2013.69.
33. Shin S, Jung I, Jung D, Kim CS, Kang SM, Ryu S et al. Novel antitumor therapeutic strategy using CD4(+) T cell-derived extracellular vesicles. Biomaterials. 2022; 289: 121765. doi: 10.1016/j.biomaterials.2022.121765.
34. Teteloshvili N, Smigielska‑Czepiel K, Kroesen BJ, Brouwer E, Kluiver J, Boots AM, van den Berg A. T-cell activation induces dynamic changes in miRNA expression patterns in CD4 and CD8 T-cell subsets. Microrna. 2015; 4 (2): 117–122. doi: 10.2174/2211536604666150819194636.
35. Xiong B, Nie Y, Yu Y, Wang S, Zuo X. Reduced miR-16 levels are associated with VEGF upregulation in high-risk myelodysplastic syndromes. J Cancer. 2021; 12 (7): 1967–1977. doi: 10.7150/jca.52455.
36. Saadh MJ, Jasim NY, Ahmed MH, Ballal S, Kumar A, Atteri S et al. Critical roles of miR-21 in promotions angiogenesis: friend or foe? Clin Exp Med. 2025; 25 (1): 66. doi: 10.1007/s10238-025-01600-7.
37. Moriondo G, Soccio P, Minoves M, Scioscia G, Tondo P, Barbaro M et al. Hypoxia mediates cancer development and progression through HIF-1a and microRNA regulation. Arch Bronconeumol. 2023; 59 (10): 629–637. doi: 10.1016/j.arbres.2023.07.001.
38. Geng Z, Li Z, Cui Z, Wang J, Yang X, Liu C. Novel bionic topography with MiR-21 coating for improving bone-implant integration through regulating cell adhesion and angiogenesis. Nano Lett. 2020; 20 (10): 7716–7721. doi: 10.1021/acs.nanolett.0c03240.
39. Geng Z, Yu Y, Li Z, Ma L, Zhu S, Liang Y et al. MiR-21 promotes osseointegration and mineralization through enhancing both osteogenic and osteoclastic expression. Mater Sci Eng C. 2020; 111: 110785. doi: 10.1016/j.msec.2020.110785.
40. Ma S, Zhang A, Li X, Zhang S, Liu S, Zhao H. MiR-21-5p regulates extracellular matrix degradation and angiogenesis in TMJOA by targeting Spry1. Arthritis Res Ther. 2020; 22: 1–17. doi: 10.1186/s13075-020-2145-y.
41. Lian C, Zhao L, Qiu J, Wang Y, Chen R, Liu Z et al. MiR-25-3p promotes endothelial cell angiogenesis in aging mice via TULA-2/SYK/VEGFR-2 downregulation. Aging (Albany NY). 2020; 12 (22): 22599–22613. doi: 10.18632/aging.103834.
42. McCoy MG, Jamaiyar A, Sausen G, Cheng HS, Perez-Cremades D, Zhuang R et al. MicroRNA-375 repression of Kruppel-like factor 5 improves angiogenesis in diabetic critical limb ischemia. Angiogenesis. 2023; 26 (1): 107–127. doi: 10.1007/s10456-022-09856-3.
43. Tsitsiou E, Lindsay MA. microRNAs and the immune response. Curr Opin Pharmacol. 2009; 9: 514–520. doi: 10.1016/j.coph.2009.05.003.
44. Du X, Hu N, Yu H, Hong L, Ran F, Huang D et al. MiR-150 regulates endothelial progenitor cell differentiation via Akt and promotes thrombus resolution. Stem Cell Res Ther. 2020; 11 (1): 354. doi: 10.1186/s13287-020-01871-9.
45. Dong Y, Alonso F, Jahjah T, Fremaux I, Grosset CF, Genot E. miR-155 regulates physiological angiogenesis but an miR-155-rich microenvironment disrupts the process by promoting unproductive endothelial sprouting. Cell Mol Life Sci. 2022; 79 (4): 208. doi: 10.1007/s00018-022-04231-3.
46. Kane NM, Howard L, Descamps B, Meloni M, McClure J, Lu R et al. Role of MicroRNAs 99b, 181a, and 181b in the differentiation of human embryonic stem cells to vascular endothelial cells. Stem Cells. 2012; 30: 643–654. doi: 10.1002/stem.1026.
47. Liu SY, Deng SY, He YB, Ni GX. MiR-451 inhibits cell growth, migration and angiogenesis in human osteosarcoma via down-regulating IL 6R. Biochem Bioph Res Co. 2017; 482 (4): 987–993. doi: 10.1016/j.bbrc.2016.11.145.
48. Bai S, Zhang G, Chen S, Wu X, Li J, Wang J et al. MicroRNA-451 regulates angiogenesis in intracerebral hemorrhage by targeting macrophage migration inhibitory factor. Mol Neurobiol. 2024; 61 (12): 10481–10499. doi: 10.1007/s12035-024-04207-3.
Review
For citations:
Tishevskaya N.V. T cells as regulators of angiogenesis (a literature review). Russian Journal of Transplantology and Artificial Organs. 2026;28(2):94-103. (In Russ.) https://doi.org/10.15825/1995-1191-2026-2-94-103
Views:
39
JATS XML
Email this article 