Impaired wound healing is associated with aging and has significant effects on human health on an individual level, but also on the whole health-care sector. Deficient angiogenesis appears to be involved in the process, but the underlying biology is still poorly understood. This is at least partially being explained by complexity and costs in using mammalian aging models. To understand aging-related vascular biology of impaired wound healing, we used zebrafish and turquoise killifish fin regeneration models. The regeneration of caudal fin after resection was significantly reduced in old individuals in both species. Age-related changes in angiogenesis, vascular density and expression levels of angiogenesis biomarker VEGF-A were observed. Furthermore, the anti-angiogenic drug vascular endothelial growth factor receptor blocking inhibitor SU5416 reduced regeneration, indicating a key role for angiogenesis in the regeneration of aging caudal fin despite aging-related changes in vasculature. Taken together, our data indicate that these fish fin regeneration models are suitable for studying aging-related decline in wound healing and associated alterations in aging vasculature.

Department of Ecology and Vertebrate Zoology University of Łódź 90136 Łódź Poland

Institute of Vertebrate Biology Czech Academy of Sciences 60365 Brno Czech Republic

Turku Bioscience Centre University of Turku and Åbo Akademi University FI 25020 Turku Finland

Zobrazit více v PubMed

Acker, T. and Plate, K. H. (2003). Role of hypoxia in tumor angiogenesis - Molecular and cellular angiogenic crosstalk. Cell Tissue Res. 314, 145-155. 10.1007/s00441-003-0763-8 PubMed DOI

Allan, C., Burel, J.-M., Moore, J., Blackburn, C., Linkert, M., Loynton, S., Macdonald, D., Moore, W. J., Neves, C., Patterson, A.et al. (2012). OMERO: flexible, model-driven data management for experimental biology. Nat. Methods 9, 245-253. 10.1038/nmeth.1896 PubMed DOI PMC

Aper, S. J. A., Van Spreeuwel, A. C. C., Van Turnhout, M. C., Van Der Linden, A. J., Pieters, P. A., Van Der Zon, N. L. L., De La Rambelje, S. L., Bouten, C. V. C. and Merkx, M. (2014). Colorful protein-based fluorescent probes for collagen imaging. PLoS ONE 9, 1-21. 10.1371/journal.pone.0114983 PubMed DOI PMC

Ashcroft, G. S., Mills, S. J. and Ashworth, J. J. (2002). Ageing and wound healing. Biogerontology 3, 337-345. 10.1023/A:1021399228395 PubMed DOI

Bankhead, P., Loughrey, M.B., Fernández, J.A., Dombrowski, Y., Mcart, D.G., Dunne, P.D., Mcquaid, S., Gray, R.T., Murray, L.J., Coleman, H.G., et al. (2017). QuPath: Open source software for digital pathology image analysis. 1-7. 10.1038/s41598-017-17204-5. PubMed DOI PMC

Bayliss, P. E., Bellavance, K. L., Whitehead, G. G., Abrams, J. M., Aegerter, S., Robbins, H. S., Cowan, D. B., Keating, M. T., O'reilly, T., Wood, J. M.et al. (2006). Chemical modulation of receptor signaling inhibits regenerative angiogenesis in adult zebrafish. Nat. Chem. Biol. 2, 265-273. 10.1038/nchembio778 PubMed DOI PMC

Blažek, R., Polačik, M. and Reichard, M. (2013). Rapid growth, early maturation and short generation time in African annual fishes. EvoDevo 4, 24. 10.1186/2041-9139-4-24 PubMed DOI PMC

Cheng, B. and Fu, X. (2018). The focus and target: angiogenesis in refractory wound healing. Int. J. Lower Extrem. Wounds 17, 301-303. 10.1177/1534734618813229 PubMed DOI

Fong, T. A., Shawver, L. K., Sun, L., Tang, C., App, H., Powell, T. J., Kim, Y. H., Schreck, R., Wang, X., Risau, W.et al. (1999). SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res. 59, 99-106. PubMed

Frykberg, R. G. and Banks, J. (2015). Challenges in the treatment of chronic wounds. Advances in Wound Care 4, 560-582. 10.1089/wound.2015.0635 PubMed DOI PMC

Gerhard, G. S., Kauffman, E. J., Wang, X., Stewart, R., Moore, J. L., Kasales, C. J., Demidenko, E. and Cheng, K. C. (2002). Life spans and senescent phenotypes in two strains of Zebrafish (Danio rerio). Exp. Gerontol. 37, 1055-1068. 10.1016/S0531-5565(02)00088-8 PubMed DOI

Goswami, A. G., Basu, S. and Shukla, V. K. (2021). Wound healing in the golden agers: what we know and the possible way ahead. Int. J. Lower Extrem. Wounds 21, 264-271. 10.1177/15347346211037841 PubMed DOI

Grunewald, M., Kumar, S., Sharife, H., Volinsky, E., Gileles-Hillel, A., Licht, T., Permyakova, A., Hinden, L., Azar, S., Friedmann, Y.et al. (2021). Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span. Science 373, eabc8479. 10.1126/science.abc8479 PubMed DOI

Harel, I. and Brunet, A. (2015). The African turquoise killifish: a model for exploring vertebrate aging and diseases in the fast lane. Cold Spring Harb. Symp. Quant. Biol. 80, 275-279. 10.1101/sqb.2015.80.027524 PubMed DOI

Hayward, A. D., Moorad, J., Regan, C. E., Berenos, C., Pilkington, J. G., Pemberton, J. M. and Nussey, D. H. (2015). Asynchrony of senescence among phenotypic traits in a wild mammal population. Exp. Gerontol. 71, 56-68. 10.1016/j.exger.2015.08.003 PubMed DOI PMC

Hellberg, C., Ostman, A. and Heldin, C.-H. (2010). PDGF and vessel maturation. Recent Results Cancer Res. 180, 103-114. PubMed

Hlushchuk, R., Dannimann, D., Correa Shokiche, C., Schaad, L., Triet, R., Jazwinska, A., Tschanz, S. A. and Djonov, V. (2016). Zebrafish caudal fin angiogenesis assay- Advanced quantitative assessment including 3-way correlative microscopy. PLoS ONE 11, e0149281. 10.1371/journal.pone.0149281 PubMed DOI PMC

Hodges, N. A., Suarez-Martinez, A. D. and Murfee, W. L. (2018). Understanding angiogenesis during aging: Opportunities for discoveries and new models. J. Appl. Physiol. 125, 1843-1850. 10.1152/japplphysiol.00112.2018 PubMed DOI PMC

Honnegowda, T. M., Kumar, P., Udupa, E. G. P., Sharan, A., Singh, R., Prasad, H. K. and Rao, P. (2015). Effects of limited access dressing in chronic wounds: A biochemical and histological study. Indian J. Plast. Surg. 48, 22-28. 10.4103/0970-0358.155263 PubMed DOI PMC

Hu, C. K. and Brunet, A. (2018). The African turquoise killifish: a research organism to study vertebrate aging and diapause. Aging Cell 17, 1-15. 10.1111/acel.12757 PubMed DOI PMC

Itou, J., Kawakami, H., Burgoyne, T. and Kawakami, Y. (2012). Life-long preservation of the regenerative capacity in the fin and heart in zebrafish. Biol. Open 1, 739-746. 10.1242/bio.20121057 PubMed DOI PMC

Kishi, S., Slack, B. E., Uchiyama, J. and Zhdanova, I. V. (2009). Zebrafish as a genetic model in biological and behavioral gerontology: Where development meets aging in vertebrates - A mini-review. Gerontology 55, 430-441. 10.1159/000228892 PubMed DOI PMC

Kumar, I., Staton, C. A., Cross, S. S., Reed, M. W. R. and Brown, N. J. . (2009). Angiogenesis, vascular endothelial growth factor and its receptors in human surgical wounds. Br. J. Surg. 96, 1484-1491. 10.1002/bjs.6778 PubMed DOI

Li, X. and Eriksson, U. (2001). Novel VEGF family members: VEGF-B, VEGF-C and VEGF-D. Int. J. Biochem. Cell Biol. 33, 421-426. 10.1016/S1357-2725(01)00027-9 PubMed DOI

Nachtrab, G., Czerwinski, M. and Poss, K. D. (2011). Sexually dimorphic fin regeneration in Zebrafish controlled by androgen/GSK3 signaling. Curr. Biol. 21, 1912-1917. 10.1016/j.cub.2011.09.050 PubMed DOI PMC

Phillips, C. J., Humphreys, I., Fletcher, J., Harding, K., Chamberlain, G. and Macey, S. (2016). Estimating the costs associated with the management of patients with chronic wounds using linked routine data. Int. Wound J. 13, 1193-1197. 10.1111/iwj.12443 PubMed DOI PMC

Polačik, M., Blažek, R. and Reichard, M. (2016). Laboratory breeding of the short-lived annual killifish Nothobranchius furzeri. Nat. Protoc. 11, 1396-1413. 10.1038/nprot.2016.080 PubMed DOI

Posnett, J. and Franks, P. J. (2008). The burden of chronic wounds in the UK. Nurs. Times 104, 44-45. PubMed

Reichard, M., Blažek, R., Dyková, I., Žák, J. and Polačik, M. (2022). Challenges in keeping annual killifish. In Laboratory Fish in Biomedical Research (ed. D'Angelo L. and de G P.), pp. 289-310. London: Academic Press.

Rivard, A., Berthou-Soulie, L., Principe, N., Kearney, M., Curry, C., Branellec, D., Semenza, G. L. and Isner, J. M. (2000). Age-dependent defect in vascular endothelial growth factor expression is associated with reduced hypoxia-inducible factor 1 activity. J. Biol. Chem. 275, 29643-29647. 10.1074/jbc.M001029200 PubMed DOI

Sammarco, M. C., Sammarco, M. C., Dawson, L. A., Schanes, P. P., Yu, L. and Muneoka, K. (2015). The mammalian blastema: regeneration at our fingertips. Regeneration 2, 93-105. 10.1002/reg2.36 PubMed DOI PMC

Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B.et al. . (2012). Fiji: An open-source platform for biological-image analysis. Nat. Methods 9, 676-682. 10.1038/nmeth.2019. PubMed DOI PMC

Sen, C. K., Gordillo, G. M., Roy, S., Kirsner, R., Lambert, L., Hunt, T. K., Gottrup, F., Gurtner, G. C. and Longaker, M. T. (2009). Human skin wounds: A major and snowballing threat to public health and the economy: PERSPECTIVE ARTICLE. Wound Repair. Regen. 17, 763-771. 10.1111/j.1524-475X.2009.00543.x PubMed DOI PMC

Sgonc, R. and Gruber, J. (2013). Age-related aspects of cutaneous wound healing: A mini-review. Gerontology 59, 159-164. 10.1159/000342344 PubMed DOI

Tsai, S. B., Tucci, V., Uchiyama, J., Fabian, N. J., Lin, M. C., Bayliss, P. E., Neuberg, D. S., Zhdanova, I. V. and Kishi, S. (2007). Differential effects of genotoxic stress on both concurrent body growth and gradual senescence in the adult zebrafish. Aging Cell 6, 209-224. 10.1111/j.1474-9726.2007.00278.x PubMed DOI

Wendler, S., Hartmann, N., Hoppe, B. and Englert, C. (2015). Age-dependent decline in fin regenerative capacity in the short-lived fish Nothobranchius furzeri. Aging Cell 14, 857-866. 10.1111/acel.12367 PubMed DOI PMC

Ye, J., Coulouris, G., Zaretskaya, I., Cutcutache, I., Rozen, S. and , Madden, T.L. (2012). Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics 13, 134. 10.1186/1471-2105-13-134. PubMed DOI PMC