Molecular Mechanism of Physical Exercise Enhances Angiogenesis Through Vascular Endothelial Growth Factor Expression: A Systematic Review

Authors

  • Novadri Ayubi Faculty of Sport and Health Sciences, Universitas Negeri Surabaya, Surabaya, Indonesia https://orcid.org/0000-0002-5196-6636
  • Junian Cahyanto Wibawa Department of Physical Education, Health and Recreation, STKIP PGRI Trenggalek, Trenggalek, Indonesia https://orcid.org/0009-0009-2597-5350
  • Anton Komaini Faculty of Sport Science, Universitas Negeri Padang, Padang, Indonesia https://orcid.org/0000-0002-2955-0175
  • Ainun Zulfikar Rizki Faculty of Sport and Health Sciences, Universitas Negeri Surabaya, Surabaya, Indonesia
  • Mohammed Aljunaid Faculty of Medicine, Taiz University, Taiz, Yemen https://orcid.org/0000-0001-6311-2534
  • Dio Alif Airlangga Daulay Faculty of Sport and Health Sciences, Universitas Negeri Surabaya, Surabaya, Indonesia https://orcid.org/0000-0002-2202-034X

Keywords:

Angiogenesis, Hypoxia, Physical exercise, Physical fitness

Abstract

Objective: The aim of this study was to examine how exercise affects human VEGF levels through a review of molecular mechanisms. Methods: This study used a systematic review method, where we searched for original articles in Scopus, PubMed, Web of Science, and Science Direct for analysis. Papers on VEGF and physical activity from 2020–2025 were searched. Furthermore, the sample included men and women aged 20 to 80 years. After a comprehensive review and observation, ten publications that met the inclusion criteria were analyzed. Ten studies found that exercise substantially increased VEGF expression. Results: This comprehensive study found that regular exercise significantly increased VEGF expression, which promotes angiogenesis. Activation of the HIF-1α pathway, stimulation of tissue hypoxia, and enhancement of signal transduction associated with blood vessel development are key molecular mechanisms involved. Conclusions: These results indicate that exercise has functional benefits and a significant impact on the molecular regulation of new blood vessel production, which aids physiological adaptation in a number of diseases, such as metabolic and cardiovascular disorders. By modifying VEGF expression, exercise is a successful non-pharmacological strategy to improve blood vessel health, according to the study.

Downloads

Download data is not yet available.

References

Champion KE, Parmenter B, McGowan C, Spring B, Wafford QE, Gardner LA, et al. Effectiveness of school-based eHealth interventions to prevent multiple lifestyle risk behaviours among adolescents: a systematic review and meta-analysis. Lancet Digit Heal. 2019;1(5):e206-e221. doi: 10.1016/S2589-7500(19)30088-3.

Abdu A, Bakrey H, Hamed M, Idris T. Non-communicable diseases in Eritrea: a review of challenges, risk factors and public health strategies. Discov Public Health. 2025;22(1). doi: 10.1186/s12982-025-00449-1.

Long KQ, Ngoc-Anh HT, Phuong NH, Tuyet-Hanh TT, Park K, Takeuchi M, et al. Clustering lifestyle risk behaviors among Vietnamese adolescents and roles of school: A Bayesian multilevel analysis of global school-based student health survey 2019. Lancet Reg Health - West Pac. 2021;15:100225. doi: 10.1016/j.lanwpc.2021.100225.

Biswas T, Townsend N, Huda MM, Maravilla J, Begum T, Pervin S, et al. Prevalence of multiple non-communicable diseases risk factors among adolescents in 140 countries: A population-based study. eClinicalMedicine. 2022;52:101591. doi: 10.1016/j.eclinm.2022.101591.

Vaduganathan M, Mensah GA, Turco JV, Fuster V, Roth GA. The global burden of cardiovascular diseases and risk: A compass for future health. J Am Coll Cardiol. 2022;80(25):2361-2371. doi: 10.1016/j.jacc.2022.11.005.

Manfroi WC, Peukert C, Berti CB, Noer C, Gutierres D de A, Silva FT. Acute myocardial infarction: the first manifestation of ischemic heart disease and relation to risk factors. Arq Bras Cardiol. 2002;78(4):392-395. doi: 10.1590/S0066-782X2002000400006,

Florek K, Mendyka D, Gomułka K. Vascular endothelial growth factor (VEGF) and its role in the cardiovascular system. Biomedicines. 2024;12(5):1-15. doi: 10.3390/biomedicines12051055.

Swaroop G. Post-myocardial infarction heart failure: A review on management of drug therapies. Cureus. 2022;14(6):14-19. doi: 10.7759/cureus.25745.

Weckbach LT, Preissner KT, Deindl E. The role of midkine in arteriogenesis, involving mechanosensing, endothelial cell proliferation, and vasodilation. Int J Mol Sci. 2018;19(9). doi: 10.3390/ijms19092559.

Wang J, Song Y, Xie W, Zhao J, Wang Y, Yu W. Therapeutic angiogenesis based on injectable hydrogel for protein delivery in ischemic heart disease. iScience. 2023;26(5):106577. doi: 10.1016/j.isci.2023.106577.

Uemura A, Fruttiger M, D'Amore PA, De Falco S, Joussen AM, Sennlaub F, et al. VEGFR1 signaling in retinal angiogenesis and microinflammation. Prog Retin Eye Res. 2021;84:100954. doi: 10.1016/j.preteyeres.2021.100954.

Braile M, Marcella S, Cristinziano L, Galdiero MR, Modestino L, Ferrara A, et al. VEGF-A in cardiomyocytes and heart diseases. Int J Mol Sci. 2020;21(15):1-18. doi: 10.3390/ijms21155294.

Lai JYM, Riley DR, Anson M, Henney A, Cuthbertson DJ, Hernadez G, et al. Cardiovascular outcomes with intravitreal anti-vascular endothelial growth factor therapy in patients with diabetes: A real-world data analysis. Diabetes Ther. 2024;15(4):833-842. doi: 10.1007/s13300-024-01544-3.

Niu J, Han X, Qi H, Yin J, Zhang Z, Zhang Z. Correlation between vascular endothelial growth factor and long-term prognosis in patients with acute myocardial infarction. Exp Ther Med. 2016;12(1):475-479. doi: 10.3892/etm.2016.3286.

Wibawa JC, Setiawan A, Pratiwi DJ, Yunitasari I, Puspitaningsih F, Dzikryet LF, al. Increased activity of the catalase enzyme after physical exercise as a signal for reducing hydrogen peroxide (H2O2): a systematic review. Fizjoterapia Pol. 2024;2024(5):232-238. doi: 10.56984/8ZG020C7GDL.

Ayubi N, Wibawa JC, Callixte C. The mechanism of physical exercise increases heat shock protein 70 (HSP70): A systemic review. Medicni Perspekt. 2024;29(4):14-22. doi: 10.26641/2307-0404.2024.4.319168.

Wibawa JC, Febrianto N, Fudin MS, Ockta Y, Festiawan R. The mechanism of physical exercise increasing glutathione peroxidase as an endogenous antioxidant: a systematic review. Retos. 2025;63:610-619. doi: 10.47197/retos.v63.108856.

Muhammed Al-Jarraha, Nour Erekatb AAK. Upregulation of vascular endothelial growth factor expression in the kidney could be reversed following treadmill exercise training in type I diabetic rats. World J Nephrol Urol. 2014;3(1):25-29. doi: 10.14740/wjnu153e.

Ramadhan NA, Tinduh D, Nugraheni N, Subadi I, Narasinta I, Melaniani S. Vascular endothelial growth factor levels: moderate versus low-intensity flow-restricted exercise. Retos. 2025;2025:254-262. doi: 10.47197/retos.v64.110307

Liu Z, Huang J, Hu M, Cui X, Leng L, Wang K, et al. Acute high-intensity interval exercise is superior to moderate-intensity continuous exercise in enhancing endothelial function and its associated biomarkers in sedentary young individuals: the possible involvement of lactate. J Exerc Sci Fit. 2025;23(1):60-68. doi: 10.1016/j.jesf.2024.12.006.

Kim HB, Seo MW, Jung HC. Effects of aerobic vs. resistance exercise on vascular function and vascular endothelial growth factor in older women. Healthcare. 2023;11(18):1-9. doi: 10.3390/healthcare11182479.

Suhr F, Knuth S, Achtzehn S, Mester J, De Marees M. Acute exhaustive exercise under normoxic and normobaric hypoxic conditions differentially regulates angiogenic biomarkers in humans. Medicine. 2021;57(7). doi: 10.3390/medicina57070727.

Huang J, Leng LU, Hu M, Cui X, Yan XU, Liu Z, et al. Comparative effects of different exercise types on cardiovascular health and executive function in sedentary young individuals. Med Sci Sports Exerc. 2025;0:1110-1122. doi: 10.1249/MSS.0000000000003645.

Górna S, Podgórski T, Kleka P, Domaszewska K. Effects of different intensities of endurance training on neurotrophin levels and functional and cognitive outcomes in post-ischaemic stroke adults: A randomised clinical trial. Int J Mol Sci. 2025;26(6):1-20. doi: 10.3390/ijms26062810.

Sofiatun, Putra DP, Rossa M, Meilani E, Dewi AK, Prayitno DA, et al. Acute effects of resistance and aerobic exercise on HIF-1α erythropoietin, and VEGF levels in women with a sedentary lifestyle: A randomized controlled trial. J Sport Heal Res. 2025;17(Supl 2):117-140.

Volga Fernandes R, Tricoli V, Garcia Soares A, Haruka Miyabara E, Saldanha Aoki M, Laurentino G. Low-load resistance exercise with blood flow restriction increases hypoxia-induced angiogenic genes expression. J Hum Kinet. 2022;84(1):82-91. doi: 10.2478/hukin-2022-0101.

Kuhne LA, Ksiezarczyk AM, Braumann KM, Reer R, Jacobs T, Röder B, et al. The effects of acute cardiovascular exercise on memory and its associations with exercise-induced increases in neurotrophic factors. Front Aging Neurosci. 2021;13:1-17. doi: 10.3389/fnagi.2021.750401.

dos Santos LL, de Castro JBP, Linhares DG, dos Santos AOB, Cordeiro LS, Borba-Pinheiro CJ,et al. Effects of physical exercise on hepatic biomarkers in adult individuals: A systematic review and meta-analysis. Retos. 2023;49:762-774. doi: 10.47197/retos.V49.98939.

de Sousa TR, da Silva Alexandrino WG, Souza A, Faúndez-Casanova C, Pascoini MJS, Awada MAM, et al. Effects of physical activity in adults with severe obesity: a systematic review. Retos. 2024;53(424):671-680. doi: 10.47197/retos.V53.102511.

Marinho DA, Ferraz R, Toubekis AG, Neiva HP. Editorial: Musculoskeletal adaptations to training and sports performance: Connecting theory and practice. Front Physiol. 2022;13:866895. doi: 10.3389/fphys.2022.866895.

Vargas-Ortiz K, Pérez-Vázquez V, Macías-Cervantes MH. Exercise and sirtuins: A way to mitochondrial health in skeletal muscle. Int J Mol Sci. 2019;20(11):1-11. doi: 10.3390/ijms20112717.

Venkatakrishnan G, Parvathi VD. Decoding the mechanism of vascular morphogenesis to explore future prospects in targeted tumor therapy. Med Oncol. 2022;39(11):1-14. doi: 10.1007/s12032-022-01810-z.

Ribatti D, Pezzella F. Overview on the different patterns of tumor vascularization. Cells. 2021;10(3):1-13. doi: 10.3390/cells10030639.

Lorenc P, Sikorska A, Molenda S, Guzniczak N, Dams-Kozlowska H, Florczak A. Physiological and tumor-associated angiogenesis: Key factors and therapy targeting VEGF/VEGFR pathway. Biomed Pharmacother. 2024;180:117585. doi: 10.1016/j.biopha.2024.117585.

Zhang J, Muri J, Fitzgerald G, Gorski T, Gianni-Barrera R, Masschelein E, et al. Endothelial lactate controls muscle regeneration from ischemia by inducing M2-like macrophage polarization. Cell Metab. 2020;31(6):1136-1153.e7. doi: 10.1016/j.cmet.2020.05.004.

Melincovici CS, Boşca AB, Şuşman S, Mărginean M, Mihu C, Istrate M, et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol. 2018;59(2):455-467. PMID: 30173249.

Wazzani R, Pallu S, Bourzac C, Ahmaïdi S, Portier H, Jaffré C. Physical activity and bone vascularization: A way to explore in bone repair context? Life. 2021;11(8):1-12. doi: 10.3390/life11080783.

Tryfonos A, Tzanis G, Pitsolis T, Karatzanos E, Koutsilieris M, Nanas S, et al. Exercise training enhances angiogenesis-related gene responses in skeletal muscle of patients with chronic heart failure. Cells. 2021;10(8). doi: 10.3390/cells10081915.

Niazi S, Tayebi SM, Costa PB, Mirdar S, Hamidian G. Effects of six weeks of high-intensity interval training on HIF-1α protein expression in lung tissues and apoptosis of pulmonary system in male Wistar rats. Ann Appl Sport Sci. 2023;11(1):1-7. doi: 10.52547/aassjournal.1203.

Pullamsetti SS, Mamazhakypov A, Weissmann N, Seeger W, Savai R. Hypoxia-inducible factor signaling in pulmonary hypertension. J Clin Invest. 2020;130(11):5638-5651. doi: 10.1172/JCI137558.

Pan J, Zhang L, Li D, Li Y, Lu M, Hu Y, et al. Hypoxia-inducible factor-1: Regulatory mechanisms and drug therapy in myocardial infarction. Eur J Pharmacol. 2024;963:176277. doi: 10.1016/j.ejphar.2023.176277.

Albadari N, Deng S, Li W. The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy. Expert Opin Drug Discov. 2019;14(7):667-682. doi: 10.1080/17460441.2019.1613370.

Mozaffaritabar S, Koltai E, Zhou L, Bori Z, Kolonics A, Kujach S, et al. PGC-1α activation boosts exercise-dependent cellular response in the skeletal muscle. J Physiol Biochem. 2024;80(2):329-335. doi: 10.1007/s13105-024-01006-1.

Dabravolski SA, Khotina VA, Omelchenko AV, Kalmykov VA, Orekhov AN. The role of the VEGF family in atherosclerosis development and its potential as treatment targets. Int J Mol Sci. 2022;23(2). doi: 10.3390/ijms23020931.

Apte RS, Chen DS, Ferrara N. VEGF in signaling and sisease: Beyond discovery and development. Cell. 2019;176(6):1248-1264. doi: 10.1016/j.cell.2019.01.021.

Ross M, Kargl CK, Ferguson R, Gavin TP, Hellsten Y. Exercise-induced skeletal muscle angiogenesis: impact of age, sex, angiocrines and cellular mediators. Eur J Appl Physiol. 2023;123(7):1415-1432. doi: 10.1007/s00421-022-05128-6.

Downloads

Published

2026-08-10

How to Cite

Ayubi, N., Wibawa, J. C., Komaini, A., Rizki, A. Z., Aljunaid, M., & Daulay, D. A. A. (2026). Molecular Mechanism of Physical Exercise Enhances Angiogenesis Through Vascular Endothelial Growth Factor Expression: A Systematic Review. Al-Rafidain Journal of Medical Sciences ( ISSN 2789-3219 ), 11(1), 275–282. Retrieved from https://ajms.iq/index.php/ALRAFIDAIN/article/view/3141

Issue

Section

Review article