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Molecular mechanisms associated with diabetic endothelial–erectile dysfunction

Nature Reviews Urology volume 13, pages 266–274 (2016)Cite this article

Subjects

Key Points

  • ED is a prevalent complication of diabetes, affecting up to 75% of all diabetic men, and is responsible for a decreased quality of life for these patients

  • Diabetic ED has a multifactorial aetiology, although cavernosal endothelial dysfunction is currently recognized as a hallmark of the disease pathophysiology

  • Diabetes-induced hyperglycaemia and oxidative stress increase are responsible for the loss of endothelial cell functionality and integrity

  • Diabetic systemic and cavernosal endothelial dysfunction is maintained owing to the detrimental effects of diabetes on the vascular repair mechanisms of angiogenesis and vasculogenesis

  • Improvements in endothelial health and amelioration of ED might be achieved by tight glycaemic control and treatment with PDE5Is and testosterone supplementation

  • Understanding the molecular pathways involved in endothelial dysfunction will aid in the identification of novel therapeutic strategies to improve endothelial and erectile function in diabetic men

Abstract

Erectile dysfunction (ED) is a common complication of diabetes, affecting up to 75% of all diabetic men. Although the aetiology of diabetic ED is multifactorial, endothelial dysfunction is recognized as a mainstay in the pathophysiology of the disease. Endothelial dysfunction is induced by the detrimental actions of high glucose levels and increased oxidative stress on endothelial cells that make up the vascular lining. Besides directly injuring the endothelium, diabetes might also hamper vascular repair mechanisms of angiogenesis and vasculogenesis. These states exacerbate and maintain endothelial dysfunction, impairing vasorelaxation events and cavernosal blood perfusion, which are crucial for normal erectile function.

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Figure 1: Diabetes, endothelial dysfunction and ED.
Figure 2: Diabetes and testosterone effects on endogenous endothelial regenerative capacity.

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References

  1. Shaw, J. E., Sicree, R. A. & Zimmet, P. Z. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res. Clin. Pract. 87, 4–14 (2010).

    CAS  PubMed  Google Scholar 

  2. Kolodny, R. C., Kahn, C. B., Goldstein, H. H. & Barnett, D. M. Sexual dysfunction in diabetic men. Diabetes 23, 306–309 (1974).

    CAS  PubMed  Google Scholar 

  3. Saenz de Tejada, I. et al. Pathophysiology of erectile dysfunction. J. Sex. Med. 2, 26–39 (2005).

    PubMed  Google Scholar 

  4. Goldstein, I. et al. Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: a multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care 26, 777–783 (2003).

    CAS  PubMed  Google Scholar 

  5. Vendeira, P., Costa, C. & Virag, R. Diabetic-associated erectile dysfunction. Eur. Endocrinol. 5, 75–80 (2009).

    Google Scholar 

  6. Vardi, Y. Microvascular complications in diabetic erectile dysfunction: do we need other alternatives? Diabetes Care 32 (Suppl. 2), S420–S422 (2009).

    PubMed  PubMed Central  Google Scholar 

  7. Musicki, B. & Burnett, A. L. Endothelial dysfunction in diabetic erectile dysfunction. Int. J. Impot. Res. 19, 129–138 (2007).

    CAS  PubMed  Google Scholar 

  8. Ahmed, N. Advanced glycation endproducts — role in pathology of diabetic complications. Diabetes Res. Clin. Pract. 67, 3–21 (2005).

    CAS  PubMed  Google Scholar 

  9. Bakker, W., Eringa, E. C., Sipkema, P. & van Hinsbergh, V. W. Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity. Cell Tissue Res. 335, 165–189 (2009).

    CAS  PubMed  Google Scholar 

  10. Costa, C. et al. Increased endothelial apoptotic cell density in human diabetic erectile tissue-comparison with clinical data. J. Sex. Med. 6, 826–835 (2009).

    PubMed  Google Scholar 

  11. Castela, A. et al. Role of oxidative stress-induced systemic and cavernosal molecular alterations in the progression of diabetic erectile dysfunction. J. Diabetes 7, 393–401 (2015).

    CAS  PubMed  Google Scholar 

  12. Costa, C. & Virag, R. The endothelial−erectile dysfunction connection: an essential update. J. Sex. Med. 6, 2390–2404 (2009).

    CAS  PubMed  Google Scholar 

  13. Bivalacqua, T. J., Usta, M. F., Champion, H. C., Kadowitz, P. J. & Hellstrom, W. J. Endothelial dysfunction in erectile dysfunction: role of the endothelium in erectile physiology and disease. J. Androl. 24 (Suppl. 6), S17–S37 (2003).

    CAS  PubMed  Google Scholar 

  14. Palumbo, P. J. Metabolic risk factors, endothelial dysfunction, and erectile dysfunction in men with diabetes. Am. J. Med. Sci. 334, 466–480 (2007).

    PubMed  Google Scholar 

  15. Vlachopoulos, C., Ioakeimidis, N., Terentes-Printzios, D. & Stefanadis, C. The triad: erectile dysfunction−endothelial dysfunction−cardiovascular disease. Curr. Pharm. Des. 14, 3700–3714 (2008).

    CAS  PubMed  Google Scholar 

  16. Gandaglia, G. et al. Erectile dysfunction as a cardiovascular risk factor in patients with diabetes. Endocrine 43, 285–292 (2013).

    CAS  PubMed  Google Scholar 

  17. Kirby, M., Jackson, G. & Simonsen, U. Endothelial dysfunction links erectile dysfunction to heart disease. Int. J. Clin. Pract. 59, 225–229 (2005).

    CAS  PubMed  Google Scholar 

  18. Heruti, R. J. et al. Erectile dysfunction severity might be associated with poor cardiovascular prognosis in diabetic men. J. Sex. Med. 4, 465–471 (2007).

    PubMed  Google Scholar 

  19. Costa, C. in Erectile Dysfunction: Causes, Risk Factors and Management (ed. Grant, P. S.) 145–165 (Nova Science Publishers, 2012).

    Google Scholar 

  20. Jones, H. J. Testosterone associations with erectile dysfunction, diabetes, and the metabolic syndrome. Eur. Urol. Suppl. 6, 847–857 (2007).

    CAS  Google Scholar 

  21. Traish, A. M., Feeley, R. J. & Guay, A. Mechanisms of obesity and related pathologies: androgen deficiency and endothelial dysfunction may be the link between obesity and erectile dysfunction. FEBS J. 276, 5755–5767 (2009).

    CAS  PubMed  Google Scholar 

  22. Martin, A., Komada, M. R. & Sane, D. C. Abnormal angiogenesis in diabetes mellitus. Med. Res. Rev. 23, 117–145 (2003).

    CAS  PubMed  Google Scholar 

  23. Esposito, K. et al. Circulating CD34+ KDR+ endothelial progenitor cells correlate with erectile function and endothelial function in overweight men. J. Sex. Med. 6, 107–114 (2009).

    PubMed  Google Scholar 

  24. Goldstein, A. M., Meehan, J. P., Morrow, J. W., Buckley, P. A. & Rogers, F. A. The fibrous skeleton of the corpora cavernosa and its probable function in the mechanism of erection. Br. J. Urol. 57, 574–578 (1985).

    CAS  PubMed  Google Scholar 

  25. Porst, H. & Sharlip, I. D. in Standard Practice in Sexual Medicine (eds Porst, H. & Buvat, J.) 31–42 (Blackwell Publishing, 2006).

    Google Scholar 

  26. Burnett, A. L., Lowenstein, C. J., Bredt, D. S., Chang, T. S. & Snyder, S. H. Nitric oxide: a physiologic mediator of penile erection. Science 257, 401–403 (1992).

    CAS  PubMed  Google Scholar 

  27. Hedlund, P. et al. Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. Proc. Natl Acad. Sci. USA 97, 2349–2354 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Andersson, K. E. Pharmacology of penile erection. Pharmacol. Rev. 53, 417–450 (2001).

    CAS  PubMed  Google Scholar 

  29. Hurt, K. J. et al. Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection. Proc. Natl Acad. Sci. USA 99, 4061–4066 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Padma-Nathan, H. et al. Pharmacotherapy for erectile dysfunction. J. Sex. Med. 1, 128–140 (2004).

    CAS  PubMed  Google Scholar 

  31. Zheng, H., Bidasee, K. R., Mayhan, W. G. & Patel, K. P. Lack of central nitric oxide triggers erectile dysfunction in diabetes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R1158–R1164 (2007).

    CAS  PubMed  Google Scholar 

  32. Hartge, M. M., Kintscher, U. & Unger, T. Endothelial dysfunction and its role in diabetic vascular disease. Endocrinol. Metab. Clin. North Am. 35, 551–560 (2006).

    CAS  PubMed  Google Scholar 

  33. Billups, K. L. Erectile dysfunction as an early sign of cardiovascular disease. Int. J. Impot. Res. 17, S19–S24 (2005).

    PubMed  Google Scholar 

  34. Kamenov, Z. A. A comprehensive review of erectile dysfunction in men with diabetes. Exp. Clin. Endocrinol. Diabetes 123, 141–158 (2015).

    CAS  PubMed  Google Scholar 

  35. Montorsi, P., Montorsi, F. & Schulman, C. C. Is erectile dysfunction the 'tip of the iceberg' of a systemic vascular disorder? Eur. Urol. 44, 352–354 (2003).

    PubMed  Google Scholar 

  36. Lerman, A. & Burnett, J. C. Jr. Intact and altered endothelium in regulation of vasomotion. Circulation 86 (Suppl. 3), III12–III19 (1992).

    CAS  PubMed  Google Scholar 

  37. Esper, R. J. et al. Endothelial dysfunction: a comprehensive appraisal. Cardiovasc. Diabetol. 5, 4 (2006).

    PubMed  PubMed Central  Google Scholar 

  38. Villar, I. C., Francis, S., Webb, A., Hobbs, A. J. & Ahluwalia, A. Novel aspects of endothelium-dependent regulation of vascular tone. Kidney Int. 70, 840–853 (2006).

    CAS  PubMed  Google Scholar 

  39. Endemann, D. H. & Schiffrin, E. L. Endothelial dysfunction. J. Am. Soc. Nephrol. 15, 1983–1992 (2004).

    CAS  PubMed  Google Scholar 

  40. Pober, J. S. & Sessa, W. C. Evolving functions of endothelial cells in inflammation. Nat. Rev. Immunol. 7, 803–815 (2007).

    CAS  PubMed  Google Scholar 

  41. Behrendt, D. & Ganz, P. Endothelial function. From vascular biology to clinical applications. Am. J. Cardiol. 90, 40L–48L (2002).

    CAS  PubMed  Google Scholar 

  42. Maxwell, A. J. Mechanisms of dysfunction of the nitric oxide pathway in vascular diseases. Nitr. Oxide 6, 101–124 (2002).

    CAS  Google Scholar 

  43. Akishita, M. et al. Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertens. Res. 30, 1029–1034 (2007).

    CAS  PubMed  Google Scholar 

  44. Guay, A. T. & Traish, A. Testosterone deficiency and risk factors in the metabolic syndrome: implications for erectile dysfunction. Urol. Clin. North Am. 38, 175–183 (2011).

    PubMed  Google Scholar 

  45. Castela, A., Vendeira, P. & Costa, C. Testosterone, endothelial health, and erectile function. ISRN Endocrinol. 2011, 839149 (2011).

    PubMed  PubMed Central  Google Scholar 

  46. Hill, J. M. et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N. Engl. J. Med. 348, 593–600 (2003).

    PubMed  Google Scholar 

  47. Loomans, C. J. et al. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes 53, 195–199 (2004).

    CAS  PubMed  Google Scholar 

  48. Costa, C. in Vasculogenesis and Angiogenesis — From Embryonic Development to Regenerative Medicine (eds Simionescu, D. T. & Simionescu, A.) 107–130 (Tech Open Access Publisher, 2011).

    Google Scholar 

  49. Costa, C. in Oxidative Stress, Inflammation and Angiogenesis in the Metabolic Syndrome (eds Soares, R. & Costa, C.) 101–121 (Springer-Verlag, 2009).

    Google Scholar 

  50. Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).

    CAS  PubMed  Google Scholar 

  51. Nowotny, K., Jung, T., Hohn, A., Weber, D. & Grune, T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 5, 194–222 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Afanas'ev, I. Signaling of reactive oxygen and nitrogen species in diabetes mellitus. Oxid. Med. Cell. Longev. 3, 361–373 (2010).

    PubMed  PubMed Central  Google Scholar 

  53. Newsholme, P. et al. Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity. J. Physiol. 583, 9–24 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Musicki, B., Kramer, M. F., Becker, R. E. & Burnett, A. L. Inactivation of phosphorylated endothelial nitric oxide synthase (Ser-1177) by O-GlcNAc in diabetes-associated erectile dysfunction. Proc. Natl Acad. Sci. USA 102, 11870–11875 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Agarwal, A., Nandipati, K. C., Sharma, R. K., Zippe, C. D. & Raina, R. Role of oxidative stress in the pathophysiological mechanism of erectile dysfunction. J. Androl. 27, 335–347 (2006).

    CAS  PubMed  Google Scholar 

  56. Carneiro, F. S. et al. Erectile dysfunction in young non-obese type II diabetic Goto-Kakizaki rats is associated with decreased eNOS phosphorylation at Ser1177. J. Sex. Med. 7, 3620–3634 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang, L. et al. AGE-breaker ALT-711 plus insulin could restore erectile function in streptozocin-induced type 1 diabetic rats. J. Sex. Med. 11, 1452–1462 (2014).

    CAS  PubMed  Google Scholar 

  58. Ryu, J. K. et al. The role of free radical in the pathogenesis of impotence in streptozotocin-induced diabetic rats. Yonsei Med. J. 44, 236–241 (2003).

    CAS  PubMed  Google Scholar 

  59. Bivalacqua, T. J. et al. Superoxide anion production in the rat penis impairs erectile function in diabetes: influence of in vivo extracellular superoxide dismutase gene therapy. J. Sex. Med. 2, 187–197; discussion 197–188 (2005).

    CAS  PubMed  Google Scholar 

  60. Angulo, J. et al. The novel antioxidant, AC3056 (2,6-di-t-butyl-4-((dimethyl-4-methoxyphenylsilyl)methyloxy)phenol), reverses erectile dysfunction in diabetic rats and improves NO-mediated responses in penile tissue from diabetic men. J. Sex. Med. 6, 373–387 (2009).

    CAS  PubMed  Google Scholar 

  61. Deng, W. et al. Superoxide dismutase — a target for gene therapeutic approach to reduce oxidative stress in erectile dysfunction. Methods Mol. Biol. 610, 213–227 (2010).

    CAS  PubMed  Google Scholar 

  62. Bivalacqua, T. J. et al. Gene transfer of endothelial nitric oxide synthase partially restores nitric oxide synthesis and erectile function in streptozotocin diabetic rats. J. Urol. 169, 1911–1917 (2003).

    CAS  PubMed  Google Scholar 

  63. Vincent, A. M., Russell, J. W., Low, P. & Feldman, E. L. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr. Rev. 25, 612–628 (2004).

    CAS  PubMed  Google Scholar 

  64. Tuncayengin, A. et al. Cavernosal tissue nitrite, nitrate, malondialdehyde and glutathione levels in diabetic and non-diabetic erectile dysfunction. Int. J. Androl. 26, 250–254 (2003).

    CAS  PubMed  Google Scholar 

  65. Zhang, W. et al. Antioxidant treatment with quercetin ameliorates erectile dysfunction in streptozotocin-induced diabetic rats. J. Biosci. Bioeng. 112, 215–218 (2011).

    CAS  PubMed  Google Scholar 

  66. Yu, W., Wan, Z., Qiu, X. F., Chen, Y. & Dai, Y. T. Resveratrol, an activator of SIRT1, restores erectile function in streptozotocin-induced diabetic rats. Asian J. Androl. 15, 646–651 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Mostafa, T., Sabry, D., Abdelaal, A. M., Mostafa, I. & Taymour, M. Cavernous antioxidant effect of green tea, epigallocatechin-3-gallate with/without sildenafil citrate intake in aged diabetic rats. Andrologia 45, 272–277 (2013).

    CAS  PubMed  Google Scholar 

  68. Wang, L. et al. Antioxidant icariside II combined with insulin restores erectile function in streptozotocin-induced type 1 diabetic rats. J. Cell. Mol. Med. 19, 960–969 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Liu, T. et al. Ginsenoside Rg3 improves erectile function in streptozotocin-induced diabetic rats. J. Sex. Med. 12, 611–620 (2015).

    CAS  PubMed  Google Scholar 

  70. Ha, U. S. et al. Cyanidin-3-O-β-D-glucopyranoside concentrated materials from mulberry fruit have a potency to protect erectile function by minimizing oxidative stress in a rat model of diabetic erectile dysfunction. Urol. Int. 88, 470–476 (2012).

    CAS  PubMed  Google Scholar 

  71. Kilarkaje, N. et al. Role of angiotensin II and angiotensin-(1−7) in diabetes-induced oxidative DNA damage in the corpus cavernosum. Fertil. Steril. 100, 226–233 (2013).

    CAS  PubMed  Google Scholar 

  72. Jin, H. R. et al. Functional and morphologic characterizations of the diabetic mouse corpus cavernosum: comparison of a multiple low-dose and a single high-dose streptozotocin protocols. J. Sex. Med. 6, 3289–3304 (2009).

    CAS  PubMed  Google Scholar 

  73. De Young, L., Yu, D., Bateman, R. M. & Brock, G. B. Oxidative stress and antioxidant therapy: their impact in diabetes-associated erectile dysfunction. J. Androl. 25, 830–836 (2004).

    PubMed  Google Scholar 

  74. Jin, H. R. et al. Intracavernous delivery of a designed angiopoietin-1 variant rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse. Diabetes 60, 969–980 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Radi, R. Protein tyrosine nitration: biochemical mechanisms and structural basis of functional effects. Acc. Chem. Res. 46, 550–559 (2013).

    CAS  PubMed  Google Scholar 

  76. Radi, R. Nitric oxide, oxidants, and protein tyrosine nitration. Proc. Natl Acad. Sci. USA 101, 4003–4008 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Fan, M. et al. Protective effects of hydrogen-rich saline against erectile dysfunction in a streptozotocin induced diabetic rat model. J. Urol. 190, 350–356 (2012).

    PubMed  Google Scholar 

  78. Liu, G. et al. Chronic administration of sildenafil modified the impaired VEGF system and improved the erectile function in rats with diabetic erectile dysfunction. J. Sex. Med. 7, 3868–3878 (2010).

    CAS  PubMed  Google Scholar 

  79. Bivalacqua, T. J. et al. RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction. Proc. Natl Acad. Sci. USA 101, 9121–9126 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Jeremy, J. Y. et al. Reactive oxygen species and erectile dysfunction: possible role of NADPH oxidase. Int. J. Impot. Res. 19, 265–280 (2007).

    CAS  PubMed  Google Scholar 

  81. Hirata, H. et al. Restoring erectile function by antioxidant therapy in diabetic rats. J. Urol. 182, 2518–2525 (2009).

    CAS  PubMed  Google Scholar 

  82. Li, W. J. et al. PARP inhibition restores erectile function by suppressing corporal smooth muscle apoptosis in diabetic rats. J. Sex. Med. 8, 1072–1082 (2011).

    CAS  PubMed  Google Scholar 

  83. Aversa, A. et al. Androgens and penile erection: evidence for a direct relationship between free testosterone and cavernous vasodilation in men with erectile dysfunction. Clin. Endocrinol. (Oxf.) 53, 517–522 (2000).

    CAS  Google Scholar 

  84. Yu, J. et al. Androgen receptor-dependent activation of endothelial nitric oxide synthase in vascular endothelial cells: role of phosphatidylinositol 3-kinase/akt pathway. Endocrinology 151, 1822–1828 (2010).

    CAS  PubMed  Google Scholar 

  85. Schultheiss, D. et al. Androgen and estrogen receptors in the human corpus cavernosum penis: immunohistochemical and cell culture results. World J. Urol. 21, 320–324 (2003).

    CAS  PubMed  Google Scholar 

  86. Torres-Estay, V. et al. Androgen receptor in human endothelial cells. J. Endocrinol. 224, R131–R137 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Heinlein, C. A. & Chang, C. The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol. Endocrinol. 16, 2181–2187 (2002).

    CAS  PubMed  Google Scholar 

  88. Murphy, J. G. & Khalil, R. A. Decreased [Ca2+]i during inhibition of coronary smooth muscle contraction by 17β-estradiol, progesterone, and testosterone. J. Pharmacol. Exp. Ther. 291, 44–52 (1999).

    CAS  PubMed  Google Scholar 

  89. Hwang, T. I. & Lin, Y. C. The relationship between hypogonadism and erectile dysfunction. Int. J. Impot. Res. 20, 231–235 (2008).

    CAS  PubMed  Google Scholar 

  90. Yamamoto, H. et al. Penile apoptosis in association with p53 under lack of testosterone. Urol. Res. 32, 9–13 (2004).

    CAS  PubMed  Google Scholar 

  91. Yildiz, O. et al. Testosterone might cause relaxation of human corpus cavernosum by potassium channel opening action. Urology 74, 229–232 (2009).

    PubMed  Google Scholar 

  92. Makhsida, N., Shah, J., Yan, G., Fisch, H. & Shabsigh, R. Hypogonadism and metabolic syndrome: implications for testosterone therapy. J. Urol. 174, 827–834 (2005).

    CAS  PubMed  Google Scholar 

  93. Boyanov, M. A., Boneva, Z. & Christov, V. G. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male 6, 1–7 (2003).

    CAS  PubMed  Google Scholar 

  94. Kapoor, D., Goodwin, E., Channer, K. S. & Jones, T. H. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur. J. Endocrinol. 154, 899–906 (2006).

    CAS  PubMed  Google Scholar 

  95. Traish, A. M., Saad, F. & Guay, A. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J. Androl. 30, 23–32 (2009).

    CAS  PubMed  Google Scholar 

  96. Morelli, A. et al. Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Endocrinology 145, 2253–2263 (2004).

    CAS  PubMed  Google Scholar 

  97. Buvat, J. et al. Hypogonadal men nonresponders to the PDE5 inhibitor tadalafil benefit from normalization of testosterone levels with a 1% hydroalcoholic testosterone gel in the treatment of erectile dysfunction (TADTEST study). J. Sex. Med. 8, 284–293 (2011).

    CAS  PubMed  Google Scholar 

  98. Aversa, A., Francomano, D. & Lenzi, A. Does testosterone supplementation increase PDE5-inhibitor responses in difficult-to-treat erectile dysfunction patients? Expert Opin. Pharmacother. 16, 625–628 (2015).

    CAS  PubMed  Google Scholar 

  99. Vignozzi, L. et al. Testosterone regulates RhoA/Rho-kinase signaling in two distinct animal models of chemical diabetes. J. Sex. Med. 4, 620–630; discussion 631–632 (2007).

    CAS  PubMed  Google Scholar 

  100. Zhang, X. H., Melman, A. & Disanto, M. E. Update on corpus cavernosum smooth muscle contractile pathways in erectile function: a role for testosterone? J. Sex. Med. 8, 1865–1879 (2011).

    CAS  PubMed  Google Scholar 

  101. Traish, A. M. et al. Effects of medical or surgical castration on erectile function in an animal model. J. Androl. 24, 381–387 (2003).

    PubMed  Google Scholar 

  102. Traish, A. M. & Guay, A. T. Are androgens critical for penile erections in humans? Examining the clinical and preclinical evidence. J. Sex. Med. 3, 382–404 (2006).

    CAS  PubMed  Google Scholar 

  103. Traish, A. M., Toselli, P., Jeong, S. J. & Kim, N. N. Adipocyte accumulation in penile corpus cavernosum of the orchiectomized rabbit: a potential mechanism for veno-occlusive dysfunction in androgen deficiency. J. Androl. 26, 242–248 (2005).

    PubMed  Google Scholar 

  104. Traish, A. M. et al. Effects of castration and androgen replacement on erectile function in a rabbit model. Endocrinology 140, 1861–1868 (1999).

    CAS  PubMed  Google Scholar 

  105. Blute, M. et al. Erectile dysfunction and testosterone deficiency. Front. Horm. Res. 37, 108–122 (2009).

    CAS  PubMed  Google Scholar 

  106. Shen, Z. J., Zhou, X. L., Lu, Y. L. & Chen, Z. D. Effect of androgen deprivation on penile ultrastructure. Asian J. Androl. 5, 33–36 (2003).

    CAS  PubMed  Google Scholar 

  107. Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1, 27–31 (1995).

    CAS  PubMed  Google Scholar 

  108. Costa, C., Soares, R. & Schmitt, F. Angiogenesis: now and then. APMIS 112, 402–412 (2004).

    PubMed  Google Scholar 

  109. Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 438, 932–936 (2005).

    CAS  PubMed  Google Scholar 

  110. Asahara, T. & Isner, J. M. Endothelial progenitor cells for vascular regeneration. J. Hematother. Stem Cell Res. 11, 171–178 (2002).

    PubMed  Google Scholar 

  111. Castela, A. et al. Differentially expressed angiogenic genes in diabetic erectile tissue — results from a microarray screening. Mol. Genet. Metab. 105, 255–262 (2012).

    CAS  PubMed  Google Scholar 

  112. Tepper, O. M. et al. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 106, 2781–2786 (2002).

    PubMed  Google Scholar 

  113. Jesmin, S. et al. Diminished penile expression of vascular endothelial growth factor and its receptors at the insulin-resistant stage of a type II diabetic rat model: a possible cause for erectile dysfunction in diabetes. J. Mol. Endocrinol. 31, 401–418 (2003).

    CAS  PubMed  Google Scholar 

  114. Maiorino, M. I. et al. Circulating endothelial progenitor cells in type 1 diabetic patients with erectile dysfunction. Endocrine 49, 415–421 (2014).

    PubMed  Google Scholar 

  115. Jin, H. R. et al. Intracavernous delivery of synthetic angiopoietin-1 protein as a novel therapeutic strategy for erectile dysfunction in the type II diabetic db/db mouse. J. Sex. Med. 7, 3635–3646 (2010).

    CAS  PubMed  Google Scholar 

  116. Kim, S. O., Lee, H. S., Ahn, K. & Park, K. COMP-angiopoietin-1 promotes cavernous angiogenesis in a type 2 diabetic rat model. J. Korean Med. Sci. 28, 725–730 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Kwon, M. H. et al. Effect of intracavernous administration of angiopoietin-4 on erectile function in the streptozotocin-induced diabetic mouse. J. Sex. Med. 10, 2912–2927 (2013).

    CAS  PubMed  Google Scholar 

  118. Dall'Era, J. E. et al. Vascular endothelial growth factor (VEGF) gene therapy using a nonviral gene delivery system improves erectile function in a diabetic rat model. Int. J. Impot. Res. 20, 307–314 (2008).

    CAS  PubMed  Google Scholar 

  119. Shirai, M. et al. Vascular endothelial growth factor restores erectile function through modulation of the insulin-like growth factor system and sex hormone receptors in diabetic rat. Biochem. Biophys. Res. Commun. 341, 755–762 (2006).

    CAS  PubMed  Google Scholar 

  120. Yamanaka, M. et al. Vascular endothelial growth factor restores erectile function through inhibition of apoptosis in diabetic rat penile crura. J. Urol. 173, 318–323 (2005).

    CAS  PubMed  Google Scholar 

  121. Rabinovsky, E. D. & Draghia-Akli, R. Insulin-like growth factor I plasmid therapy promotes in vivo angiogenesis. Mol. Ther. 9, 46–55 (2004).

    CAS  PubMed  Google Scholar 

  122. Kim, M., Hwang, E. C., Park, I. K. & Park, K. Insulin-like growth factor-1 gene delivery may enhance the proliferation of human corpus cavernosal smooth muscle cells. Urology 76, 511.e5–511.e9 (2010).

    Google Scholar 

  123. Kuhn, M. et al. The natriuretic peptide/guanylyl cyclase — a system functions as a stress-responsive regulator of angiogenesis in mice. J. Clin. Invest. 119, 2019–2030 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Pu, X. Y., Hu, L. Q., Wang, H. P., Luo, Y. X. & Wang, X. H. Improvement in erectile dysfunction after insulin-like growth factor-1 gene therapy in diabetic rats. Asian J. Androl. 9, 83–91 (2007).

    CAS  PubMed  Google Scholar 

  125. Asahara, T. et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ. Res. 85, 221–228 (1999).

    CAS  PubMed  Google Scholar 

  126. Aicher, A. et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat. Med. 9, 1370–1376 (2003).

    CAS  PubMed  Google Scholar 

  127. Urbich, C. & Dimmeler, S. Endothelial progenitor cells: characterization and role in vascular biology. Circ. Res. 95, 343–353 (2004).

    CAS  PubMed  Google Scholar 

  128. Urbich, C. et al. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J. Mol. Cell. Cardiol. 39, 733–742 (2005).

    CAS  PubMed  Google Scholar 

  129. Heil, M., Ziegelhoeffer, T., Mees, B. & Schaper, W. A different outlook on the role of bone marrow stem cells in vascular growth: bone marrow delivers software not hardware. Circ. Res. 94, 573–574 (2004).

    CAS  PubMed  Google Scholar 

  130. Baumhakel, M., Werner, N., Bohm, M. & Nickenig, G. Circulating endothelial progenitor cells correlate with erectile function in patients with coronary heart disease. Eur. Heart J. 27, 2184–2188 (2006).

    PubMed  Google Scholar 

  131. Jialal, I., Devaraj, S., Singh, U. & Huet, B. A. Decreased number and impaired functionality of endothelial progenitor cells in subjects with metabolic syndrome: implications for increased cardiovascular risk. Atherosclerosis 211, 297–302 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Kim, K. A. et al. High glucose condition induces autophagy in endothelial progenitor cells contributing to angiogenic impairment. Biol. Pharm. Bull. 37, 1248–1252 (2014).

    CAS  PubMed  Google Scholar 

  133. Callaghan, M. J., Ceradini, D. J. & Gurtner, G. C. Hyperglycemia-induced reactive oxygen species and impaired endothelial progenitor cell function. Antioxid. Redox Signal. 7, 1476–1482 (2005).

    CAS  PubMed  Google Scholar 

  134. Oikawa, A. et al. Diabetes mellitus induces bone marrow microangiopathy. Arterioscler. Thromb. Vasc. Biol. 30, 498–508 (2010).

    CAS  PubMed  Google Scholar 

  135. Li, H. et al. Advanced glycation end products impair the migration, adhesion and secretion potentials of late endothelial progenitor cells. Cardiovasc. Diabetol. 11, 46 (2012).

    PubMed  PubMed Central  Google Scholar 

  136. Westerweel, P. E. et al. Impaired endothelial progenitor cell mobilization and dysfunctional bone marrow stroma in diabetes mellitus. PLoS ONE 8, e60357 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Fadini, G. P. et al. Diabetes impairs progenitor cell mobilisation after hindlimb ischaemia-reperfusion injury in rats. Diabetologia 49, 3075–3084 (2006).

    CAS  PubMed  Google Scholar 

  138. Gallagher, K. A. et al. Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1α. J. Clin. Invest. 117, 1249–1259 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Avogaro, A., Fadini, G. P., Gallo, A., Pagnin, E. & de Kreutzenberg, S. Endothelial dysfunction in type 2 diabetes mellitus. Nutr. Metab. Cardiovasc. Dis. 16, (Suppl. 2) S39–S45 (2006).

    CAS  PubMed  Google Scholar 

  140. De Falco, E. et al. Altered SDF-1-mediated differentiation of bone marrow-derived endothelial progenitor cells in diabetes mellitus. J. Cell. Mol. Med. 13, 3405–3414 (2009).

    PubMed  Google Scholar 

  141. Hamed, S., Brenner, B. & Roguin, A. Nitric oxide: a key factor behind the dysfunctionality of endothelial progenitor cells in diabetes mellitus type-2. Cardiovasc. Res. 91, 9–15 (2011).

    CAS  PubMed  Google Scholar 

  142. Kuki, S. et al. Hyperglycemia accelerated endothelial progenitor cell senescence via the activation of p38 mitogen-activated protein kinase. Circ. J. 70, 1076–1081 (2006).

    CAS  PubMed  Google Scholar 

  143. Chen, J. et al. Advanced glycation endproducts alter functions and promote apoptosis in endothelial progenitor cells through receptor for advanced glycation endproducts mediate overpression of cell oxidant stress. Mol. Cell. Biochem. 335, 137–146 (2010).

    CAS  PubMed  Google Scholar 

  144. Foresta, C. et al. Circulating endothelial progenitor cells in subjects with erectile dysfunction. Int. J. Impot. Res. 17, 288–290 (2005).

    CAS  PubMed  Google Scholar 

  145. Foresta, C. et al. Increased levels of osteocalcin-positive endothelial progenitor cells in patients affected by erectile dysfunction and cavernous atherosclerosis. J. Sex. Med. 7, 751–757 (2010).

    CAS  PubMed  Google Scholar 

  146. Murata, M. et al. Endothelial impairment and bone marrow-derived CD34+/133+ cells in diabetic patients with erectile dysfunction. J. Diabetes Investig. 3, 526–533 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Mantalaris, A. et al. Localization of androgen receptor expression in human bone marrow. J. Pathol. 193, 361–366 (2001).

    CAS  PubMed  Google Scholar 

  148. Foresta, C. et al. Androgens stimulate endothelial progenitor cells through an androgen receptor-mediated pathway. Clin. Endocrinol. (Oxf.) 68, 284–289 (2008).

    CAS  Google Scholar 

  149. Foresta, C. et al. Reduced number of circulating endothelial progenitor cells in hypogonadal men. J. Clin. Endocrinol. Metab. 91, 4599–4602 (2006).

    CAS  PubMed  Google Scholar 

  150. Desouza, C. V. Does drug therapy reverse endothelial progenitor cell dysfunction in diabetes? J. Diabetes Complications 27, 519–525 (2013).

    PubMed  Google Scholar 

  151. Foresta, C. et al. The PDE5 inhibitor sildenafil increases circulating endothelial progenitor cells and CXCR4 expression. J. Sex. Med. 6, 369–372 (2009).

    CAS  PubMed  Google Scholar 

  152. Foresta, C. et al. Relationship between vascular damage degrees and endothelial progenitor cells in patients with erectile dysfunction: effect of vardenafil administration and PDE5 expression in the bone marrow. Eur. Urol. 51, 1411–1419 (2007).

    CAS  PubMed  Google Scholar 

  153. Foresta, C. et al. Circulating endothelial progenitor cells and endothelial function after chronic Tadalafil treatment in subjects with erectile dysfunction. Int. J. Impot. Res. 18, 484–488 (2006).

    CAS  PubMed  Google Scholar 

  154. Fadini, G. P. et al. Optimized glycaemic control achieved with add-on basal insulin therapy improves indexes of endothelial damage and regeneration in type 2 diabetic patients with macroangiopathy: a randomized crossover trial comparing detemir versus glargine. Diabetes Obes. Metab. 13, 718–725 (2011).

    CAS  PubMed  Google Scholar 

  155. Hortenhuber, T. et al. Endothelial progenitor cells are related to glycemic control in children with type 1 diabetes over time. Diabetes Care 36, 1647–1653 (2013).

    PubMed  PubMed Central  Google Scholar 

  156. Gou, X. et al. Transplantation of endothelial progenitor cells transfected with VEGF165 to restore erectile function in diabetic rats. Asian J. Androl. 13, 332–338 (2011).

    CAS  PubMed  Google Scholar 

  157. Gilbert, R. E. Augmenting endothelial repair in diabetes: role of bone marrow-derived cells. Can. J. Diabetes 37, 315–318 (2013).

    PubMed  Google Scholar 

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  1. Department of Biochemistry, Faculty of Medicine, University of Porto, Al. Prof Hernâni Monteiro, 4200–319, Porto, Portugal

    Ângela Castela & Carla Costa

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Castela, Â., Costa, C. Molecular mechanisms associated with diabetic endothelial–erectile dysfunction. Nat Rev Urol 13, 266–274 (2016). https://doi.org/10.1038/nrurol.2016.23

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