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26 February, 2020

HYPOXIA, KEY IN TENDINOPATHY

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Tendinopathy is one of the most common injuries in elite sport. An editorial published (Järvinen, 2019) by Dr. Tero Järvinen in the prestigious British Journal of Sports Medicine magazine, focuses on a key element of the injured tissue: hypoxia. Due to low levels of oxygen, this damaged area presents, even at rest, a high lactate concentration (Alfredson et al.,2002), as well as anaerobic enzymes, and fibrotic and hyaline tissue (Järvinen et al., 1997).

These biological and histopathological characteristics, make hypoxia chronic, which causes the activation of the HIF-1α, a transcription factor that adaptatively regulates to the changes in the oxygen concentration in tissues. HIF-1α stabilizes quickly, when levels of intracellular oxygen decrease, modulating the protein related to the anaerobic metabolism and the creation of new blood vessels (neovascularization) through vascular growth factors (e.g. VEGF) (Pouysségur, Dayan, & Mazure, 2006). Paradoxically, these angiogenic (i.e. creation of new blood vessels), aberrant and chaotic signals induced by hypoxia create a net of new blood vessels, which do not help solve the problem, but rather perpetuate it. This process is known as pathological vascularization, similar to what takes place in the tumour (high lactate concentration, hypoxia and heterogeneous vascular net) (De Palma, Biziato, & Petrova, 2017).

Due to this situation, one of the goals should be normalizing blood flow to raise the amount of oxygen reaching the damaged tissue. Recent studies have tried to reverse this situation by reintroducing factors that are required for a vascular stabilization in the injured zone, like R-RAS protein (Li, Sawada, & Komatsu, 2017). Other proposals relate to exercise as a tool to normalize vascularization. For example, in animal cancer models, exercise increases blood flow to the tumour, reducing hypoxia, lactate concentration and vasoconstriction (Koelwyn et al., 2017; McCullough et al., 2014). Following this method, it is proven that exercise is able to modulate the tumour surroundings. By transferring these results to the tendon, an exercise protocol could increase the injury blood flow, reducing hypoxia, as well as the pathophysiological aspects related to it.

Professor Järvinen says “Oxygen is an absolute requirement for tissue regeneration in a human body”. A key concept to have in mind for injuries (tendinous and non-tendinous), taking into account the amount of oxygen which flows into the damaged tissue.

 

Adrián Castillo García

 

 

References

 

Alfredson, H., Bjur, D., Thorsen, K., Lorentzon, R., & Sandström, P. (2002). High intratendinous lactate levels in painful chronic Achilles tendinosis. An investigation using microdialysis technique. Journal of Orthopaedic Research, 20(5), 934–938. https://doi.org/10.1016/S0736-0266(02)00021-9

De Palma, M., Biziato, D., & Petrova, T. V. (2017). Microenvironmental regulation of tumour angiogenesis. Nature Reviews Cancer, 17, 457. Retrieved from https://doi.org/10.1038/nrc.2017.51

Järvinen, M., Józsa, L., Kannus, P., Järvinen, T. L. N., Kvist, M., & Leadbetter, W. (1997). Histopathological findings in chronic tendon disorders. Scandinavian Journal of Medicine & Science in Sports, 7(2), 86–95. https://doi.org/10.1111/j.1600-0838.1997.tb00124.x

Järvinen, T. A. H. (2019). Neovascularisation in tendinopathy: from eradication to stabilisation? British Journal of Sports Medicine, bjsports-2019-100608. https://doi.org/10.1136/bjsports-2019-100608

Koelwyn, G. J., Quail, D. F., Zhang, X., White, R. M., & Jones, L. W. (2017). Exercise-dependent regulation of the tumour microenvironment. Nature Reviews Cancer, 17, 620. Retrieved from https://doi.org/10.1038/nrc.2017.78

Li, F., Sawada, J., & Komatsu, M. (2017). R-Ras-Akt axis induces endothelial lumenogenesis and regulates the patency of regenerating vasculature. Nature Communications, 8(1), 1720. https://doi.org/10.1038/s41467-017-01865-x

McCullough, D. J., Stabley, J. N., Siemann, D. W., & Behnke, B. J. (2014). Modulation of Blood Flow, Hypoxia, and Vascular Function in Orthotopic Prostate Tumors During Exercise. JNCI: Journal of the National Cancer Institute, 106(4). https://doi.org/10.1093/jnci/dju036

Pouysségur, J., Dayan, F., & Mazure, N. M. (2006). Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature, 441(7092), 437–443. https://doi.org/10.1038/nature04871

 

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