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Increasing Vascular Response to Injury Improves Tendon Early Healing Outcome in Aged Rats

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Abstract

Tendon injuries positively correlate with patient age, as aging has significant effects on tendon homeostatic maintenance and healing potential after injury. Vascularity is also influenced by age, with both clinical and animal studies demonstrating reduced blood flow in aged tissues. However, it is unknown how aging effects vascularity following tendon injury, and if this vascular response can be modulated through the delivery of angiogenic factors. Therefore, the objective of this study is to evaluate the vascular response following Achilles tendon injury in adult and aged rats, and to define the alterations to tendon healing in an aged model following injection of angiogenic factors. It was determined that aged rat Achilles tendons have a reduced angiogenesis following injury. Further, the delivery of vascular endothelial growth factor, VEGF, caused an increase in vascular response to tendon injury and improved mechanical outcome in this aged population. This work suggests that reduced angiogenic potential with aging may be contributing to impaired tendon healing response and that the delivery of angiogenic factors can rescue this impaired response. This study was also the first to relate changes in vascular response in an aged model using in vivo measures of blood perfusion to alterations in healing properties.

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References

  1. Ackerman, J. E., I. Bah, J. H. Jonason, M. R. Buckley, and A. E. Loiselle. Aging does not alter tendon mechanical properties during homeostasis, but does impair flexor tendon healing. J. Orthop. Res. 35(12):2716–2724, 2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ahluwalia, A., J. Narula, M. K. Jones, X. Deng, and A. S. Tarnawski. Impaired angiogenesis in aging myocardial microvascular endothelial cells is associated with reduced importin alpha and decreased nuclear transport of HIF1 alpha: mechanistic implications. J. Physiol. Pharmacol. 61:133–139, 2010

    CAS  PubMed  Google Scholar 

  3. Arnesen, S. M., and M. A. Lawson. Age-related changes in focal adhesions lead to altered cell behavior in tendon fibroblasts. Mech. Ageing Dev. 127:726–732, 2006

    Article  CAS  PubMed  Google Scholar 

  4. Barros, L. F., and R. Belfort Jr. The effects of the subconjunctival injection of bevacizumab (Avastin) on angiogenesis in the rat cornea. Anais da Academia Brasileira de Ciencias. 79:389–394, 2007

    Article  CAS  PubMed  Google Scholar 

  5. Basu, G., H. Downey, S. Guo, A. Israel, A. Asmar, B. Hargrave, and R. Heller. Prevention of distal flap necrosis in a rat random skin flap model by gene electro transfer delivering VEGF(165) plasmid. J. Gene Med. 16:55–65, 2014

    Article  CAS  PubMed  Google Scholar 

  6. Bouis, D., Y. Kusumanto, C. Meijer, N. H. Mulder, and G. A. Hospers. A review on pro- and anti-angiogenic factors as targets of clinical intervention. Pharmacol. Res. 53:89–103, 2006

    Article  CAS  PubMed  Google Scholar 

  7. Chereddy, K. K., A. Lopes, S. Koussoroplis, V. Payen, C. Moia, H. Zhu, P. Sonveaux, P. Carmeliet, A. Des Rieux, G. Vandermeulen, and V. Preat. Combined effects of PLGA and vascular endothelial growth factor promote the healing of non-diabetic and diabetic wounds. Nanomedicine. 11:1975–1984, 2015

    Article  CAS  PubMed  Google Scholar 

  8. Corral, C. J., A. Siddiqui, L. Wu, C. L. Farrell, D. Lyons, and T. A. Mustoe. Vascular endothelial growth factor is more important than basic fibroblastic growth factor during ischemic wound healing. Arch. Surg. 134:200–205, 1999

    Article  CAS  PubMed  Google Scholar 

  9. Emami, M. J., F. M. Jaberi, N. Azarpira, A. R. Vosoughi, and N. Tanideh. Prevention of arthrofibrosis by monoclonal antibody against vascular endothelial growth factor: a novel use of bevacizumab in rabbits. Orthop. Traumatol. Surg. Res. 98:759–764, 2012

    Article  CAS  PubMed  Google Scholar 

  10. Falcon, B. L., H. Hashizume, P. Koumoutsakos, J. Chou, J. V. Bready, A. Coxon, J. D. Oliner, and D. M. McDonald. Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels. Am. J. Pathol. 175:2159–2170, 2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fevata, M. Scarless Healing in the Fetus: Implications and Strategies for Postnatal Tendon Repair. Philadelphia: University of Pennsylvania, 2006

    Google Scholar 

  12. Frontera, W. R. Physiologic changes of the musculoskeletal system with aging: a brief review. Phys. Med. Rehabil. Clin. N. Am. 28:705–711, 2017

    Article  PubMed  Google Scholar 

  13. Funakoshi, T., N. Iwasaki, T. Kamishima, M. Nishida, Y. Ito, M. Kondo, and A. Minami. In vivo visualization of vascular patterns of rotator cuff tears using contrast-enhanced ultrasound. Am. J. Sports Med. 38:2464–2471, 2010

    Article  PubMed  Google Scholar 

  14. Garcia, T., W. J. Hornof, and M. F. Insana. On the ultrasonic properties of tendon. Ultrasound Med. Biol. 29:1787–1797, 2003

    Article  PubMed  Google Scholar 

  15. Gennaro, G., C. Menard, S. E. Michaud, and A. Rivard. Age-dependent impairment of reendothelialization after arterial injury: role of vascular endothelial growth factor. Circulation. 107:230–233, 2003

    Article  PubMed  Google Scholar 

  16. Ju, Y. J., H. Tohyama, E. Kondo, T. Yoshikawa, T. Muneta, K. Shinomiya, and K. Yasuda. Effects of local administration of vascular endothelial growth factor on properties of the in situ frozen-thawed anterior cruciate ligament in rabbits. Am. J. Sports Med. 34:84–91, 2006

    Article  PubMed  Google Scholar 

  17. Kaux, J. F., L. Janssen, P. Drion, B. Nusgens, V. Libertiaux, F. Pascon, A. Heyeres, A. Hoffmann, C. Lambert, C. Le Goff, V. Denoel, J. O. Defraigne, M. Rickert, J. M. Crielaard, and A. Colige. Vascular endothelial growth factor-111 (VEGF-111) and tendon healing: preliminary results in a rat model of tendon injury. Muscles Ligaments Tendons J. 4:24–28, 2014

    Article  PubMed  PubMed Central  Google Scholar 

  18. Kostrominova, T. Y., and S. V. Brooks. Age-related changes in structure and extracellular matrix protein expression levels in rat tendons. Age (Dordr). 35:2203–2214, 2013

    Article  CAS  Google Scholar 

  19. Kryger, Z., F. Zhang, T. Dogan, C. Cheng, W. C. Lineaweaver, and H. J. Buncke. The effects of VEGF on survival of a random flap in the rat: examination of various routes of administration. Br. J. Plast. Surg. 53:234–239, 2000

    Article  CAS  PubMed  Google Scholar 

  20. LaCroix, A. S., S. E. Duenwald-Kuehl, S. Brickson, T. L. Akins, G. Diffee, J. Aiken, R. Vanderby Jr., and R. S. Lakes. Effect of age and exercise on the viscoelastic properties of rat tail tendon. Ann. Biomed. Eng. 41:1120–1128, 2013

    Article  PubMed  PubMed Central  Google Scholar 

  21. Langberg, H., J. Olesen, D. Skovgaard, and M. Kjaer. Age related blood flow around the Achilles tendon during exercise in humans. Eur. J. Appl. Physiol. 84:246–248, 2001

    Article  CAS  PubMed  Google Scholar 

  22. Manzano, R. P., G. A. Peyman, P. Khan, and M. Kivilcim. Testing intravitreal toxicity of bevacizumab (Avastin). Retina. 26:257–261, 2006

    Article  PubMed  Google Scholar 

  23. Marqueti, R. C., J. L. Q. Durigan, A. J. S. Oliveira, M. S. Mekaro, V. Guzzoni, A. A. Aro, E. R. Pimentel, and H. S. Selistre-de-Araujo. Effects of aging and resistance training in rat tendon remodeling. FASEB J. 32(1):353–368, 2017

    Article  PubMed  CAS  Google Scholar 

  24. Marquez-Arabia, W. H., J. Gomez-Hoyos, M. Gomez, I. Florez, J. A. Gallo, F. Monsalve, L. F. Arias, and H. D. Martin. Influence of aging on microvascular supply of the gluteus medius tendon: a cadaveric and histologic study. Arthroscopy. 33:1354–1360, 2017

    Article  PubMed  Google Scholar 

  25. McCarthy, M. M., and J. A. Hannafin. The mature athlete: aging tendon and ligament. Sports Health. 6:41–48, 2014

    Article  PubMed  PubMed Central  Google Scholar 

  26. Needles, A., M. Arditi, N. G. Rognin, J. Mehi, T. Coulthard, C. Bilan-Tracey, E. Gaud, P. Frinking, D. Hirson, and F. S. Foster. Nonlinear contrast imaging with an array-based micro-ultrasound system. Ultrasound Med. Biol. 36:2097–2106, 2010

    Article  CAS  PubMed  Google Scholar 

  27. Needles, A., A. Heinmiller, J. Sun, C. Theodoropoulos, D. Bates, D. Hirson, M. Yin, and F. S. Foster. Development and initial application of a fully integrated photoacoustic micro-ultrasound system. IEEE Trans. Ultrason. Ferroelectr. Freq. Control. 60:888–897, 2013

    Article  PubMed  Google Scholar 

  28. Okada, Y., T. Akisue, H. Hara, K. Kishimoto, T. Kawamoto, M. Imabori, S. Kishimoto, N. Fukase, Y. Onishi, and M. Kurosaka. The effect of bevacizumab on tumour growth of malignant fibrous histiocytoma in an animal model. Anticancer Res. 30:3391–3395, 2010

    CAS  PubMed  Google Scholar 

  29. Plate, J. F., P. J. Brown, J. Walters, J. A. Clark, T. L. Smith, M. T. Freehill, C. J. Tuohy, J. D. Stitzel, and S. Mannava. Advanced age diminishes tendon-to-bone healing in a rat model of rotator cuff repair. Am. J. Sports Med. 42:859–868, 2014

    Article  PubMed  Google Scholar 

  30. Plate, J. F., W. F. Wiggins, P. Haubruck, A. T. Scott, T. L. Smith, K. R. Saul, and S. Mannava. Normal aging alters in vivo passive biomechanical response of the rat gastrocnemius-Achilles muscle-tendon unit. J. Biomech. 46:450–455, 2013

    Article  PubMed  Google Scholar 

  31. Riggin, C. N., M. Chen, J. A. Gordon, S. M. Schultz, L. J. Soslowsky, and V. Khoury. Ultrasound-guided dry needling of the healthy rat supraspinatus tendon elicits early healing without causing permanent damage. J. Orthop. Res. 37:2035–2042, 2019

    Article  PubMed  PubMed Central  Google Scholar 

  32. Riggin, C. N., A. B. Rodriguez, S. N. Weiss, H. A. Raja, M. Chen, S. M. Schultz, C. M. Sehgal, and L. J. Soslowsky. Modulation of vascular response after injury in the rat Achilles tendon alters healing capacity. J. Orthop. Res. 39:2000–2016, 2021

    Article  CAS  PubMed  Google Scholar 

  33. Riggin, C. N., J. J. Sarver, B. R. Freedman, S. J. Thomas, and L. J. Soslowsky. Analysis of collagen organization in mouse achilles tendon using high-frequency ultrasound imaging. J. Biomech. Eng. 136:021029, 2014

    Article  PubMed  Google Scholar 

  34. Riggin, C. N., S. M. Schultz, C. M. Sehgal, and L. J. Soslowsky. Ultrasound evaluation of anti-vascular endothelial growth factor-induced changes in vascular response following tendon injury. Ultrasound Med. Biol. 45:1841–1849, 2019

    Article  PubMed  PubMed Central  Google Scholar 

  35. Rivard, A., L. Berthou-Soulie, N. Principe, M. Kearney, C. Curry, D. Branellec, G. L. Semenza, and J. M. Isner. Age-dependent defect in vascular endothelial growth factor expression is associated with reduced hypoxia-inducible factor 1 activity. J. Biol. Chem. 275:29643–29647, 2000

    Article  CAS  PubMed  Google Scholar 

  36. Rivard, A., J. E. Fabre, M. Silver, D. Chen, T. Murohara, M. Kearney, M. Magner, T. Asahara, and J. M. Isner. Age-dependent impairment of angiogenesis. Circulation. 99:111–120, 1999

    Article  CAS  PubMed  Google Scholar 

  37. Rudzki, J. R., R. S. Adler, R. F. Warren, W. R. Kadrmas, N. Verma, A. D. Pearle, S. Lyman, and S. Fealy. Contrast-enhanced ultrasound characterization of the vascularity of the rotator cuff tendon: age- and activity-related changes in the intact asymptomatic rotator cuff. J. Shoulder Elbow Surg. 17:96S-100S, 2008

    Article  PubMed  Google Scholar 

  38. Sadoun, E., and M. J. Reed. Impaired angiogenesis in aging is associated with alterations in vessel density, matrix composition, inflammatory response, and growth factor expression. J. Histochem. Cytochem. 51:1119–1130, 2003

    Article  CAS  PubMed  Google Scholar 

  39. Sehgal, C. M., P. H. Arger, A. C. Silver, J. A. Patton, H. M. Saunders, A. Bhattacharyya, and C. P. Bell. Renal blood flow changes induced with endothelin-1 and fenoldopam mesylate at quantitative Doppler US: initial results in a canine study. Radiology. 219:419–426, 2001

    Article  CAS  PubMed  Google Scholar 

  40. Takayama, K., Y. Kawakami, Y. Mifune, T. Matsumoto, Y. Tang, J. H. Cummins, N. Greco, R. Kuroda, M. Kurosaka, B. Wang, F. H. Fu, and J. Huard. The effect of blocking angiogenesis on anterior cruciate ligament healing following stem cell transplantation. Biomaterials. 60:9–19, 2015

    Article  CAS  PubMed  Google Scholar 

  41. Tempfer, H., A. Kaser-Eichberger, C. Lehner, R. Gehwolf, S. Korntner, N. Kunkel, A. Wagner, M. Gruetz, L. M. Heindl, F. Schroedl, and A. Traweger. Bevacizumab improves achilles tendon repair in a rat model. Cell Physiol. Biochem. 46:1148–1158, 2018

    Article  CAS  PubMed  Google Scholar 

  42. Torricelli, P., F. Veronesi, S. Pagani, N. Maffulli, S. Masiero, A. Frizziero, and M. Fini. In vitro tenocyte metabolism in aging and oestrogen deficiency. Age (Dordr). 35:2125–2136, 2013

    Article  CAS  Google Scholar 

  43. Turan, A., M. A. Teber, Z. I. Yakut, H. A. Unlu, and B. Hekimoglu. Sonoelastographic assessment of the age-related changes of the Achilles tendon. Med. Ultrason. 17:58–61, 2015

    Article  PubMed  Google Scholar 

  44. Uefuji, A., T. Matsumoto, T. Matsushita, T. Ueha, S. Zhang, M. Kurosaka, and R. Kuroda. Age-related differences in anterior cruciate ligament remnant vascular-derived cells. Am. J. Sports Med. 42:1478–1486, 2014

    Article  PubMed  Google Scholar 

  45. Wang, H., J. A. Keiser, B. Olszewski, W. Rosebury, A. Robertson, I. Kovesdi, and D. Gordon. Delayed angiogenesis in aging rats and therapeutic effect of adenoviral gene transfer of VEGF. Int. J. Mol. Med. 13:581–587, 2004

    CAS  PubMed  Google Scholar 

  46. World Health Organization. World Report on Ageing and Health. Geneva: World Health Organization, 2015

    Google Scholar 

  47. Yu, T. Y., J. H. Pang, K. P. Wu, M. J. Chen, C. H. Chen, and W. C. Tsai. Aging is associated with increased activities of matrix metalloproteinase-2 and -9 in tenocytes. BMC Musculoskelet. Disord. 14:2, 2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang, F., H. Liu, F. Stile, M. P. Lei, Y. Pang, T. M. Oswald, J. Beck, W. Dorsett-Martin, and W. C. Lineaweaver. Effect of vascular endothelial growth factor on rat Achilles tendon healing. Plast. Reconstr. Surg. 112:1613–1619, 2003

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was funded by an NIH/NIAMS (Grant No. P30AR069619) supported Penn Center for Musculoskeletal Disorders Imaging Seed Grant, an NIH T32 Rheumatology Training Grant (Grant No. 4T32AR007442-29) and an NSF Graduate Research Fellowship. The aged Fischer 344 rats were provided by the NIH National Institute on Aging. There are no other conflicts of interest.

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Authors and Affiliations

  1. McKay Orthopaedic Research Laboratory, University of Pennsylvania, 307A Stemmler Hall, 36th Street & Hamilton Walk, Philadelphia, PA, 19104, USA

    Corinne N. Riggin, Stephanie N. Weiss, Ashley B. Rodriguez, Harina Raja, Mengcun Chen & Louis J. Soslowsky

  2. Department of Radiology, University of Pennsylvania, 1 Silverstein, 3400 Spruce Street, Philadelphia, PA, 19104, USA

    Susan M. Schultz & Chandra M. Sehgal

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  1. Corinne N. Riggin
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  2. Stephanie N. Weiss
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Correspondence to Louis J. Soslowsky.

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Associate Editor Shayn Peirce-Cottler oversaw the review of this article.

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Riggin, C.N., Weiss, S.N., Rodriguez, A.B. et al. Increasing Vascular Response to Injury Improves Tendon Early Healing Outcome in Aged Rats. Ann Biomed Eng 50, 587–600 (2022). https://doi.org/10.1007/s10439-022-02948-7

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