Abstract
Erectile dysfunction (ED) is a common problem in aged men; however, the molecular events involved in aging ED remain unclear. To better characterize the effects of aging in the penis, we evaluated cavernosal tissue remodeling capability and the downstream activation of the intracellular signaling mediator mitogen-activated protein p42/44 kinase (p42/44 MAPK). We used male Wistar rats, which were divided in groups of 2, 6, 12, 18, and 24 months old. Penile tissues were harvested and processed for protein isolation and immunohistochemical analysis. Cavernosal viability was assessed by TUNEL assay, and proliferation was analyzed by immunohistochemical detection of proliferating cell nuclear antigen (PCNA). Immunolocalization of the activated form of p42/44 MAPK was evaluated by immunofluorescence, and changes in its phosphorylation status were quantified by western blotting. p42/44 phosphorylation profile was also assessed in situ in human young and elderly cavernosal samples. With the advancement of age, experimental cavernosal tissue remodeling was affected by an age-dependent unbalance between the rate of apoptosis and proliferation, in all erectile components. Moreover, this turnover alteration was accompanied by significant modifications in the activation profile of the downstream effector p42/44 MAPK. In the youngest corporeal samples, p42/44 was mostly activated at perivascular sites, potentially mediating cell survival/proliferation. However, in elderly experimental erectile tissue, p42/44 phosphorylation shifted to trabecular fibroblasts, indicating a potential role in extracellular matrix (ECM) production. More importantly, the same differential pattern of p42/44 activation was observed in human young and aged cavernosal fragments, suggesting a distinct function of this protein with aging. We provided evidence for the first time that with the advancement of age, there is a differential activation of p42/44 MAPK in cavernosal tissue, which may promote ECM expansion and fibrosis, therefore compromising erectile function in the elderly.
Similar content being viewed by others
References
Bakircioglu ME, Sievert KD, Nunes L, Lau A, Lin CS, Lue TF (2001) Decreased trabecular smooth muscle and caveolin-1 expression in the penile tissue of aged rats. J Urol 166:734–738
Calabrò A, Italiano G, Pescatori ES, Marin A, Gaetano O, Abatangelo G, Abatangelo G, Pagano F (1996) Physiological aging and penile erectile function: a study in the rat. Eur Urol 29:240–244
Costa C, Vendeira P (2008) Does erectile tissue angioarchitecture modify with aging? An immunohistological and morphometric approach. J Sex Med 5:833–840
Costa C, Virag R (2009) The endothelial-erectile dysfunction connection: an essential update. J Sex Med 6:2390–2404
Costa C, Soares R, Castela A, Adães S, Hastert V, Vendeira P, Virag R (2009) Increased endothelial apoptotic cell density in human diabetic erectile tissue—comparison with clinical data. J Sex Med 6:826–835
Diokno AC, Brown MB, Herzog AR (1990) Sexual function in the elderly. Arch Intern Med 150:197–200
Feldman HA, Johannes CB, Derby CA, Kleinman KP, Mohr BA, Araujo AB, McKinlay JB (2000) Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male Aging Study. Prev Med 30:328–338
Ferrini MG, Kovanecz I, Sanchez S, Vernet D, Davila HH, Rajfer J, Gonzalez-Cadavid NF (2007) Long-term continuous treatment with sildenafil ameliorates aging-related erectile dysfunction and the underlying corporal fibrosis in the rat. Biol Reprod 76:915–923
Goldstein AM, Padma-Nathan H (1990) The microarchitecture of the intracavernosal smooth muscle and the cavernosal fibrous skeleton. J Urol 144:1144–1146
He S, Liu X, Yang Y, Huang W, Xu S, Yang S, Zhang X, Roberts MS (2010) Mechanisms of MAPK pathway mediating TGF-beta(1)/Smad signal in keloid fibroblasts. Br J Dermatol 162:538–546
Ikeyama S, Kokkonen G, Shack S, Wang XT, Holbrook NJ (2002) Loss in oxidative stress tolerance with aging linked to reduced extracellular signal-regulated kinase and Akt kinase activities. FASEB J 16:114–116
Lin JS, Tsai YS, Lin YM, Lin CS, Chow NH (2001) Age-associated changes in collagen content and its subtypes within rat corpora cavernosa with computerized histomorphometric analysis. Urology 57:837–842
Mirone V, Imbimbo C, Fusco F, Verze P, Creta M, Tajana G (2009) Androgens and morphologic remodeling at penile and cardiovascular levels: a common piece in complicated puzzles? Eur Urol 56:309–316
Montorsi F, Briganti A, Salonia A, Deho' F, Zanni G, Cestari A, Guazzoni G, Rigatti P, Stief C (2003) The ageing male and erectile dysfunction. BJU Int 92:516–520
Moreland RB (2000) Pathophysiology of erectile dysfunction: the contributions of trabecular structure to function and the role of functional antagonism. Int J Impot Res 12(Suppl 4):S39–S46
Papakrivopoulou J, Lindahl GE, Bishop JE, Laurent GJ (2004) Differential roles of extracellular signal-regulated kinase 1/2 and p38MAPK in mechanical load-induced procollagen alpha1(I) gene expression in cardiac fibroblasts. Cardiovasc Res 61:736–744
Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22:153–183
Rajasekaran M, Kasyan A, Allilain W, Monga M (2003) Ex vivo expression of angiogenic growth factors and their receptors in human penile cavernosal cells. J Androl 24:85–90
Ryu JK, Han JY, Chu YC, Song SU, Lee KH, Yoon SM, Suh JK, Kim SJ (2004) Expression of cavernous transforming growth factor-beta1 and its type II receptor in patients with erectile dysfunction. Int J Androl 27:42–49
Shabsigh R, Raymond JF, Olsson CA, O'Toole K, Buttyan R (1998) Androgen induction of DNA synthesis in the rat penis. Urology 52:723–728
Siroky MB, Azadzoi KM (2003) Vasculogenic erectile dysfunction: newer therapeutic strategies. J Urol 170:S24–S29
Sommer F, Klotz T, Steinritz D, Schmidt A, Addicks K, Engelmann U, Bloch W (2002) MAP kinase 1/2 (Erk 1/2) and serine/threonine specific protein kinase Akt/PKB expression and activity in the human corpus cavernosum. Int J Impot Res 14(217):225
Tanno M, Ogihara M, Taguchi T (1996) Age-related changes in proliferating cell nuclear antigen levels. Mech Ageing Dev 92:53–66
Tarhan F, Demirel GY, Kuyumcuoğlu U, Faydaci G, Eryildirim B (2009) Apoptosis of corpus cavernosum in patients with organic erectile dysfunction. World J Urol 27:235–240
Travison TG, Shabsigh R, Araujo AB, Kupelian V, O'Donnell AB, McKinlay JB (2007) The natural progression and remission of erectile dysfunction: results from the Massachusetts Male Aging Study. J Urol 177:241–246
Wespes E (2002) Smooth muscle pathology and erectile dysfunction. Int J Impot Res 14(Suppl 1):S17–S21
Wespes E, Goes PM, Schiffmann S, Depierreux M, Vanderhaeghen JJ, Schulman CC (1991) Computerized analysis of smooth muscle fibers in potent and impotent patients. J Urol 146:1015–1017
Yamanaka M, Shirai M, Shiina H, Shirai M, Tanaka Y, Fujime M, Okuyama A, Dahiya R (2002) Loss of anti-apoptotic genes in aging rat crura. J Urol 168:2296–2300
Acknowledgement
CC was supported by the Portuguese Foundation for Science and Technology (“Compromisso com a Ciência 2007”).
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Castela, Â., Soares, R., Rocha, F. et al. Erectile tissue molecular alterations with aging—differential activation of the p42/44 MAP Kinase pathway. AGE 33, 119–130 (2011). https://doi.org/10.1007/s11357-010-9167-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11357-010-9167-3