Electron micrographs of normal penile vascular endothelium (a) and the effect of diabetes in the rabbit (b). Note the ragged appearance of the endothelium and the deposition of red (rb) and white (wb) blood cells in diabetes. (Micrographs published by the Dr. Ian Eardley in Pathophysiology of erectile dysfunction. (2002). British Journal of Diabetes and Vascular Disease , Vol. 2, No. 4, pp. 272-6, ISSN 1474-6514, by courtesy of Sullivan, M. 

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... diabetes and it is in relation with several pathogenic mechanisms in diabetes disease involved in precipitating and maintaining the ED. As it is showed in the figure 2, the physiopathology of ED in DM is multifactorial and in the following section, we address some of these pathophysiological mechanisms being so far taken into account to explain the development of ED in DM. Several clinical and laboratory studies demonstrate that endothelial dysfunction is an important mechanism for the development of ED associated with T2DM. ED is usually described as a decrease in the bioavailability of NO, as a result of decreased expression and/or activity of eNOS, including increased removal of NO. Damage to the endothelium- dependent vasoreactivity has been demonstrated in various animal models of T2DM. Myograph in vitro studies in mice fed with a high fat diet, db/db diabetic mice and obese Zucker rats have shown that the ability of muscle relaxation of the cavernous tissue decreases even when stimulated with acetylcholine (Luttrell et al., 2008; Wingard et al., 2007; Xie et al., 2007). Jesmin et al., observed a decrease of the immunofluorescent staining of eNOS and the expression of this enzyme in the penile tissue of Long-Evans Tokushima Otsuka obese rats, with respect to controls (Jesmin et al., 2003). The decrease in eNOS mRNA expression suggests that reduced expression of eNOS is initiated at the gene transcription level. The alteration in the eNOS activation is another mechanism that contributes to decreased bioavailability of NO. eNOS activation occurs through phosphorylation of serine-177 residue by serine/threonine protein kinase Akt. In turn, the Akt-dependent pathway regulates the phosphorylation of eNOS mediated by the vascular endothelial growth factor (VEGF). The effects of VEGF include proliferation, migration, angiogenesis, and antiapoptosis in endothelial cells. VEGF increased the phosphorylation and expression of antiapoptotic proteins, mediated by eNOS. It is considered that in the ED, vascular repair mechanisms mediated by VEGF are damaged, probably because the expression of the VEGF and its receptors are altered in the cavernous endothelium, conditioning its angiogenic functions (Costa & Vendeira, 2007). In addition to the decreased eNOS activity, the increased removal of NO by free radicals and oxidative agents has been shown to be important in the cavernous endothelial dysfunction in diabetes-associated ED models (Hidalgo-Tamola & Chitaley, 2009). Endothelins (ET) are potent vasoconstrictor peptides that stimulate the contraction of trabecular smooth muscle of the corpus cavernosum. No one knows the exact involvement of ET on the pathogenesis of ED. High levels of ET-1 observed in diabetic patients could be enough to cause ED, although this does not happen. However, the high intracellular calcium concentration resulting from this condition modulates gene expression sufficiently to cause the proliferation of smooth muscle. Alternatively, alterations in ET receptor sensitivity in conditions such as diabetes and hypertension can enhance the processes of vasoconstriction. It is possible that the ET system may be relevant in ED, but under certain conditions where there is global endothelial dysfunction, such as diabetes and systemic sclerosis, the use of ET antagonists in these patients could be beneficial (Ritchie & Sullivan, 2010). Maintenance of cavernosal vasodilation has been hypothesized to occur through the activation of eNOS in endothelial cells, presumably in response to shear stress. Data from animal models of T2DM support the findings of impaired vasodilation in T2DM humans. Accompanying the impaired vasodilatory response, total penile NOS activity was found to be decreased in the BBZ/WOR rat model (Vernet et al., 1995). Similar result was showed by an age-matched case controlled study of 30 patients with T2DM and ED, where was found impaired the cavernosal vasodilation (De Angelis et al., 2001). Vascular disease is probably the most common cause of ED, and of all the vascular causes, the commonest is atherosclerosis; however, DM joined with other risk factors, namely smoking, hypertension and hyperlipidaemia are also indirectly associated with the development of ED (Fig.3). A reduced arterial inflow leads to relative hypoxia within the penis with subsequent cellular effects. The crucial cellular mediator appears to be TGF- β 1, which is increased in hypoxia and induces trophic changes in the cavernosal smooth muscle, and failure of the venous-occlusive mechanism (Feldman et al., 1994; Johannes et al., 2000). On the other hand, DM can injure cells and cause ED in a direct way. Diabetes damage the endothelium impairs the vascular response of the penis to neural stimuli. The structural changes in the endothelium that are produced by diabetes are accompanied by functional changes that result in impaired smooth muscle relaxation (Cartledge et al., 2001a; Saenz de Tejada et al., 1989). In the figure 4, it is possible observe the alteration of penile vascular endothelium of the rabbit with DM. In ED, venous-occlusive dysfunction or venous leakage, involves the premature escape of blood inside the corpuses cavernous by incompetence of their drainage system and subsequent inability to reach the intracavernous pressure necessary to provide an effective stiffness. By Doppler studies and Pharmacocavernosometry, it has been observed that a high percentage of patients with T2DM present venous leak (Colakoglu et al., 1999; Metro & Broderick, 1999). Evidence from animal studies has demonstrated the importance of venous- occlusive dysfunction in the development of ED in T2DM. It is considered that the alteration in the process of veno-occlusion may be caused by changes in the structure of the penis, the cells and/or the content of the extracellular matrix. In this regard, the expression of VEGF has broad implications in the structure of the penis, resulting in changes in the rate of apoptosis. The decrease in VEGF expression correlates with elevated levels of pro-apoptotic proteins such as Bcl-2, so it is suggested that the decrease of VEGF in penile tissue in T2DM increases apoptosis and loss of erectile cells. In other studies with animal models of T2DM, there has been observed an alteration in the expression of collagen and the rate of smooth muscle/collagen in cavernous tissue. Likewise, decreased elastin has been found in the corpus cavernosum, specifically, decreased expression of tropoelastin mRNA, precursor protein of elastin and fibrillin-1. Structural alterations in the tunica albuginea caused by T2DM, could affect the compliance of the corpus cavernosum, required for veno-occlusion and intracavernous pressure maintenance (Hidalgo-Tamola & Chitaley, 2009). Clinical and biochemical evidence support the participation of the microangiopathic complications of diabetes in the pathogenesis of ED. Multiple studies have shown that chronic hyperglycemia (which is the main determinant of the microangiopathic complications) is a strong risk factor for ED. Diabetes duration and other microvascular complications (i.e. retinopathy, neuropathy and nephropathy) are predictors of the occurrence of ED (Bhasin et al., 2007). Somatic and autonomic nerve dysfunction is present in a large percentage of individuals with diabetes-associated ED (Chitaley et al., 2009). Its presence is demonstrated by the existence of both, longer latencies in the evoked potentials of pudendal nerves and abnormal bulbar urethral and urethroanal reflexes. Diabetes causes degeneration of the nitrergic nerves, which participates in the nitric oxide-dependent cavernosal smooth muscle relaxation. A central neuropathic mechanism has been postulated by several authors (Costabile, 2003). Some of the biochemical mechanisms that induce endothelial dysfunction and decreased generation of nitric oxide participate also in the pathogenesis of diabetic neuropathy (Gur et al., 2009). An example is the oxidative stress. Superoxide radicals are present in high amount in cavernosal tissues. Superoxide anion reacts with nitric oxide to form peroxynitrite resulting in decreased nitric oxide bioavailability (Boulton et al., 2004). In addition peroxynitrite is a highly toxic compound for vascular cells and neurons. It causes mitochondrial dysfunction, oxidative DNA damage and apoptosis. Other examples are the activation of protein kinase C and the presence of advance glycation end-products (AGEs). 1,2-Diacylglycerol (DAG), a metabolite responsible of lipotoxicity in obesity and T2DM, activates protein kinase C (in particular the  isoform (PKC-  ). These enzymes participate in multiple biological networks. This enzyme is activated also by free radicals. Experimental data suggest that activated PKC-  plays a major role in the hyperglycemia-related tissular damage; one of the possible explanations is the induction of the nuclear kappa B pathway. It is also involved in the carvernosal corpus smooth muscle contraction. On the other hand, chronic hyperglycemia causes the formation of AGEs which induces tissue damage by modifying molecules, activating inflammation and stimulating the synthesis of growth factors. AGEs modify cytoskeletal and myelin structure (England & Asbury, 2004). These changes correlate with a reduction in myelinated fiber density in peripheral nerves. Also, AGEs quench endothelium derived nitric oxide. As result, AGEs decreases smooth muscle relaxation and impairs erectile function (Thorve et al., 2011). The macrovascular complications during the DM contribute to the development of ED (Chai et al., 2009). Vascular atherosclerotic disease of penile arteries is present in 70-80% of cases with ED. Occlusion of the cavernosal arteries could be a contributing factor in the long term. However, recent studies have shown that structural arterial changes in the penile vascular bed could exist even in cases with ED free of coronary heart disease. ...