Erectile dysfunction in the type II diabetic db/db mouse: impaired venoocclusion with altered cavernosal vasoreactivity and matrix

Abstract

Luttrell IP, Swee M, Starcher B, Parks WC, Chitaley K. Erectile dysfunction in the type II diabetic db/db mouse: impaired venoocclusion with altered cavernosal vasoreactivity and matrix. Am J Physiol Heart Circ Physiol 294: H2204-H2211, 2008. First published March 7, 2008 doi:10.1152/ajpheart.00027.2008.-The number of men with type II diabetes-associated erectile dysfunction (ED) continues to grow rapidly; however, the majority of basic science studies has examined mechanisms of ED in animal models of type I diabetes. In this study, we first establish an in vivo mouse model of type II diabetic ED using the leptin receptor mutated db/db and wild-type control BKS mouse. Furthermore, we hypothesized that dual mechanistic impairments contribute to the impaired erectile function in the type II diabetic mouse, altered vasoreactivity, and venoocclusive disorder. In vivo erectile function was measured as intracavernosal pressure (ICP) normalized to mean arterial pressure (MAP) following electrical stimulation of the cavernosal nerve. Venoocclusion was assessed by the maintenance of elevated in vivo ICP following intracorporal saline infusion. Vasoreactivity of isolated cavernosum in response to contractile and dilatory stimulation was examined in vitro by myography. Collagen and elastin content were evaluated by quantification of hydroxyproline and desmosine, respectively, as well as by quantitative PCR and histological analysis of isolated cavernosum. Erectile function was significantly decreased in db/db vs. BKS mice in a manner consistent with impairments in venoocclusive ability and decreased inflow. Heightened vasoconstriction and attenuated dilation in cavernosum of db/db vs. BKS mice suggest an overall lowered relaxation ability and thus impaired filling of the cavernosal spaces. A decrease in desmosine and hydroxyproline as well as lowered mRNA levels for tropoelastin, fibrillin-1, and ␣1(I) collagen were detected. These vasoreactive and sinusoidal matrix alterations may alter tissue compliance dispensability, preventing the normal expansion necessary for erection. matrix; elastin; collagen; penis IN TYPE II DIABETIC patients, erectile dysfunction (ED) is associated with risk factors such as neuropathy, vascular disease, smoking, and poor lifestyle conditions such as inactivity and obesity, which are components of the metabolic syndrome (1,8). Although many studies have examined ED associated with type I diabetes, few studies have examined underlying mechanisms of decreased erectile function in animal models of type II diabetes.The penile circulation is unique in that it is composed of arterioles that supply a network of collagenous sinusoidal cavities lined with endothelial and smooth muscle cells. During sexual arousal or nocturnal tumescence, the synthesis of nitric oxide (NO) by the neuronal NO synthase, located in nonadrenergic/noncholinergic nerves, initiates cavernosal smooth muscle relaxation (2, 3). The dilation of the cavernosal arteriolar and sinusoidal smooth muscle permits increased penile blood fl...

Differential structural and functional changes in penile and coronary arteries from obese Zucker rats

“…These differences can be ascribed to the more deleterious effect of the elevated plasma glucose levels in established diabetes compared with the mild hypergylcemia found in the prediabetic OZR. On the other hand, dilatations to ACh were more severely impaired in PAs from OZRs than in the corpus cavernosum from db/db mice (30), which is in agreement with that reported for human PAs and the corpus cavernosum from diabetic patients (1). The differential impairment of endothelial function in PAs and the corpus cavernosum may be due to the different contribution of the various endothelial factors, i.e., NO, prostanoids, and EDHF, to the relaxations of penile vascular tissues (1,40).…”

“…This reduction of the smooth muscle content would be consistent with the reduced contractility found in the PAs of OZRs in the present study. On the other hand, a recent study (30) in the type 2 diabetic db/db mouse also reported matrix alterations in the corpora cavernosa consisting of dysregulation of the collagen and elastin content and associated with impaired venoocclusion and reduced erectile responses. Therefore, remodeling of penile tissues, both arterial and corporal, correlates with ED in metabolic syndrome and type 2 diabetes (28,30).…”

“…The reduced maximal contractile responses elicited by both KPSS and norepinephrine in PAs from OZRs probably reflect the smaller size of these arteries due to the structural remodeling, although the sensitivity to norepinephrine was augmented. Enhanced vasoconstrictor responses to both nerve-released norepinephrine (5,30) and to ␣ 1 -adrenergic agonists (30,50) have been demonstrated in the corpus cavernosum of OZRs and of type 2 diabetic mice, and they have been ascribed to both prejunctional and postjunctional mechanisms. In the present study, basal levels of NO appear to be insufficient to counterbalance vasoconstriction in both PAs and CAs from OZRs, since blockade of NOS failed to enhance contractions induced by either norepinephrine or by 5-HT, respectively, in contrast to that observed in control arteries.…”

Lipoprotein Receptor–Related Protein 1 Regulates Collagen 1 Expression, Proteolysis, and Migration in Human Pleural Mesothelial Cells

“…Hydroxyproline analyses were performed as previously described (24,25). Conditioned media were collected from serum-starved RPMCs and HPMCs treated with PBS or TGF-b in the presence or absence of uPA and/or RAP at 37 8 C for 48 hours.…”

Beneficial Effect of the Soluble Guanylyl Cyclase Stimulator BAY 41-2272 on Impaired Penile Erection in db/db−/− Type II Diabetic and Obese Mice

“…The db/db 2/2 mice lack leptin receptors, and this deficiency contributes to the development of both diabetes and obesity. Therefore, these mice are widely considered an appropriate model for DM2, which has been used for the study of DM2-associated ED (Luttrell et al, 2008). In addition, db/db 2/2 mice develop hyperglycemia and hyperinsulinemia, the latter of which raises resting sympathetic output and contributes to impaired cavernosal relaxation (Anderson et al, 1991).…”