Endothelial dysfunction in diabetic erectile dysfunction

Abstract

Erectile dysfunction (ED) is highly prevalent in diabetes mellitus. Pathophysiological mechanisms underlying diabetes-associated ED are in large part due to endothelial dysfunction, which functionally refers to the inability of the endothelium to produce vasorelaxing messengers and to maintain vasodilation and vascular homeostasis. The precise mechanisms leading to endothelial dysfunction in the diabetic vasculature, including the penis, are not yet fully understood. Hyperglycemia affects endothelial nitric oxide synthase activity and nitric oxide production/ bioavailability, nitric oxide-independent relaxing factors, oxidative stress, production and/or action of hormones, growth factors and/or cytokines, and generation and activity of opposing vasoconstrictors. Considering recent advances in the field of vascular biology and diabetes, the emphasis in this review is placed on the mechanisms of hyperglycemia-induced endothelial dysfunction in the pathophysiology of diabetes-associated ED.

cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action

“…In many forms of vascular disease, there is an imbalance among steps in the pathway. Low levels of NO production caused by endothelial dysfunction is a widespread medical problem that occurs in patients with metabolic syndrome, hypertension, hypercholesterolemia, diabetes, and other maladies (Celermajer et al, 1993;Musicki and Burnett, 2007;Gratzke et al, 2010). In other instances (e.g., restenosis of blood vessels or penile priapism), levels and functions of target proteins such as PKG or PDEs are altered (Celermajer et al, 1993;Kugiyama et al, 1996;Lincoln et al, 2001;Champion et al, 2005).…”

Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse

“…The multiple factors causing diabetic ED contribute to reduced responsiveness to currently available oral phosphodiesterase-5 (PDE5) inhibitors, which enhance the nitric oxide (NO)-cGMP pathway by inhibiting the breakdown of cGMP (7). The severity of endothelial dysfunction and peripheral neuropathy are mainly responsible for the poor responsiveness of diabetic patients to PDE5 inhibitors (8,9). Because the effects of PDE5 inhibitors depend on endogenous NO formation, PDE5 inhibitors fail to increase the cGMP level above the threshold required for penile erection if bioavailable NO is insufficient as the result of severe endothelial dysfunction or peripheral neuropathy (9).…”

Pharmacological Prevention and Reversion of Erectile Dysfunction After Radical Prostatectomy, by Modulation of Nitric Oxide/cGMP Pathways

“…It is logical to assume that these changes are the main cause of the impairment of corporal compliance seen in these models, both in organ bath and in vivo in the response to electrical field stimulation [53,54]. In contrast, the relative contribution of corporal endothelial dysfunction, extrapolated from the prevailing views in vascular atherosclerosis research, has not been histologically or mechanistically evaluated conclusively in impotent men or animal models of ED [55][56][57]. It is surprising that long-term insulin treatment of the WT mouse, which normalized glycemia, was only partially effective to prevent excessive collagen deposition and apoptosis.…”

“…this renders PD a sort of orphan disease in terms of a scientifi cally rational approach to therapy, in contrast to the other types of fibrosis where, in general, clinical use is supported by promising preclinical studies. 48,56 However, among the putative endogenous mechanisms of defense against fibrosis that are postulated to operate in the PD plaque, the most intensively studied and highly promising in terms of therapeutic potential is the spontaneous induction of inducible nitric oxide synthase (inOs), a nOs isoform that is not expressed in normal penile tissue. 57 whereas in the past it was assumed that the presence of inOs portended a deleterious outcome to a tissue, it is now believed to in fact be a protective mechanism against tissue fibrosis in certain settings.…”