Probable Interaction of MMP-2 and VEGF in Testicular Deteriorations Related to Aging

Year 2019, Volume: 46 Issue: 4, 735 - 741, 15.12.2019

Servet Kizildag Ferda Hosgorler , Basar Koc Ozgur Golgelioglu Guven Guvendi Sevim Kandis Mehmet Ates Nazan Uysal

https://doi.org/10.5798/dicletip.661276

Abstract

Objective: In the elderly, erectile dysfunction and hypogonadism have become more important due to the extension of human life. The most important morphological changes of the aged testis are associated with vascular deterioration, chronic hypoxia, fibrosis and hormonal changes. Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloproteinase-2 (MMP-2) are directly related to these changes along with sperm motility and viability. The contribution of VEGF and MMP-2 to the structural and functional disturbances in the aged testis is unknown. The aim of this study was to determine VEGF and MMP-2 levels in the elderly testis and their interactions with one another.
Method: The testis tissues of aged rats (26-30 months) and adult rats (8-10 months) were analysed using the ELISA method to determine MMP-2 and VEGF levels. Serum total testosterone levels were analyzed using the immunoassay method. The statistical analysis was performed using the Mann Whitney-U test, p<0.05 was considered significant. The results were presented with median and percentile values.
Results: In contrast to the adult testis, we observed that VEGF levels were increased [0.18(0.16-0.20) to 0.30(0.28-0.32) g/mg respectively, p=0.009] and MMP-2 levels decreased [3.70 (2.07-4.74) to 1,10 (1,08-1,29) g/mg respectively, p=0.03] in the aged testis. Serum total testosterone levels were lower in the aged group [5.45 (4.04-6.95) and 2.48 (1.93-3.11) ng/ml, p=0.004].
Conclusion: Low levels of MMP-2 are consistent with deficiency of reproductive function but interestingly, VEGF levels were found to be high. MMPs have the potential to regulate the levels and activities of hormones. The absence of physiological effects of VEGF may be associated with MMP-2 deficiency. The therapeutic benefit of induction of MMP-2 activity in testicular hypogonadism is open to research.

Keywords

Aging, Hypogonadism, Matrix Metalloproteinase-2 (MMP-2)

References

• 1. Gokce MI, Yaman O. Erectile dysfunction in the elderly male. Turk J Urol 2017; 43: 247-51. 2. Ryu J-K, Suh J-K. Regenerative technology for future therapy of erectile dysfunction. Transl Androl Urol 2012; 1: 173-80. 3. Ergun S, Kilic N, Fiedler W, et al. Vascular endothelial growth factor and its receptors in normal human testicular tissue. Mol Cell Endocrinol 1997; 131: 9-20. 4. Santiago J, Silva JV, Alves MG, et al. Testicular aging: an overview of ultrastructural, cellular and molecular alterations. J Gerontol A Biol Sci Med Sci 2019; 74: 860-71. 5. Regadera J, Nistal M, Paniagua R. Testis, epididymis, and spermatic cord in elderly men. Correlation of angiographic and histologic studies with systemic arteriosclerosis. Arch Pathol Lab Med 1985; 109: 663-7. 6. Guo H, Zhou H, Lu J, et al. Vascular endothelial growth factor: an attractive target in the treatment of hypoxic/ischemic brain injury. Neural Regen Res 2016; 11: 174-9. 7. Yan-Ping D, Xiao-Qin G, Xiao Ping M, et al. Effects of Chronic Exposure to Sodium Arsenite on Expressions of VEGF and VEGFR2 Proteins in the Epididymis of Rats. Biomed Res Int 2017; 2017: 2597256. 8. Tian R, Yang S, Zhu Y, et al. VEGF/VEGFR2 Signaling Regulates Germ Cell Proliferation in vitro and Promotes Mouse Testicular Regeneration in vivo. Cells Tissues Organs 2016; 201: 1-13. 9. Mittal R, Patel AP, Debs LH, et al. Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions. J Cell Physiol 2016; 231: 2599-621. 10. Donato Anthony J, Machin Daniel R, Lesniewski Lisa A. Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease. Circ Res 2018; 123: 825-48. 11. Liu Y, Zhang H, Yan L, et al. MMP-2 and MMP-9 contribute to the angiogenic effect produced by hypoxia/15-HETE in pulmonary endothelial cells. J Mol Cell Cardiol 2018; 121: 36-50. 12. Warinrak C, Wu JT, Hsu WL, et al. Expression of matrix metalloproteinases (MMP-2, MMP-9) and their inhibitors (TIMP-1, TIMP-2) in canine testis, epididymis and semen. Reprod Domest Anim 2015; 50: 48-57. 13. Belardin LB, Antoniassi MP, Camargo M, et al. Semen levels of matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinases (TIMP) protein families members in men with high and low sperm DNA fragmentation. Sci Rep 2019; 9: 10234. 14. Kohler I, Meier R, Busato A, et al. Is carbon dioxide (CO2) a useful short acting anaesthetic for small laboratory animals? Lab Anim 1999; 33: 155-61. Dicle Tıp Dergisi / Dicle Med J (2019) 46 (4) : 735 - 741 15. Pop OT, Cotoi CG, Plesea IE, et al. Correlations between intralobular interstitial morphological changes and epithelial changes in ageing testis. Rom J Morphol Embryol 2011; 52: 339-47. 16. Lee HC, Tsai SJ. Endocrine targets of hypoxia-inducible factors. J Endocrinol 2017; 234: R53-R65. 17. Basaria S. Reproductive aging in men. Endocrinol Metab Clin North Am 2013; 42: 255-70. 18. Zhang G, Kang Y, Zhou C, et al. Amelioratory Effects of Testosterone Propionate on Age-related Renal Fibrosis via Suppression of TGF-beta1/Smad Signaling and Activation of Nrf2-ARE Signaling. Sci Rep 2018; 8: 10726. 19. Chung CC, Hsu RC, Kao YH, et al. Androgen attenuates cardiac fibroblasts activations through modulations of transforming growth factor-beta and angiotensin II signaling. Int J Cardiol 2014; 176: 386-93. 20. Zhang J, Salamonsen LA. Expression of hypoxia-inducible factors in human endometrium and suppression of matrix metalloproteinases under hypoxic conditions do not support a major role for hypoxia in regulating tissue breakdown at menstruation. Hum Reprod 2002; 17: 265-74. 21. Belardin LB, Antoniassi MP, Camargo M, et al. Semen levels of matrix metalloproteinase (MMP) and tissue inhibitor of metallorproteinases (TIMP) protein families members in men with high and low sperm DNA fragmentation. Sci Rep 2019; 9: 903. 22. Marneros AG. Effects of chronically increased VEGF-A on the aging heart. FASEB J 2018; 32: 1550-65. 23. Kozhevnikova OS, Fursova AZ, Markovets AM, et al. VEGF and PEDF levels in the rat retina: effects of aging and AMD-like retinopathy. Adv Gerontol 2018; 31: 339-44. 24. Barratt SL, Blythe T, Ourradi K, et al. Effects of hypoxia and hyperoxia on the differential expression of VEGF-A isoforms and receptors in Idiopathic Pulmonary Fibrosis (IPF). Respir Res 2018; 19: 9. 25. Sounni NE, Roghi C, Chabottaux V, et al. Up-regulation of vascular endothelial growth factor-A by active membrane-type 1 matrix metalloproteinase through activation of Src-tyrosine kinases. J Biol Chem 2004; 279: 13564-13574. 26. Ferrara N. Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action. Mol Biol Cell 2010; 21: 687-90. 27. Lee S, Jilani SM, Nikolova GV, et al. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol 2005; 169: 681-91. 28. Ebrahem Q, Chaurasia SS, Vasanji A, et al. Cross-talk between vascular endothelial growth factor and matrix metalloproteinases in the induction of neovascularization in vivo. Am J Pathol 2010; 176: 496-503. 29. Lee RJ, Springer ML, Blanco-Bose WE, et al. VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation 2000; 102: 898-901. 30. Melincovici CS, Boşca AB, Şuşman S, et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol 2018; 59: 455-67.