Reduction of Endothelial and Smooth Muscle Density in the Corpora Cavernosa of the Streptozotocin Induced Diabetic Rat

Introduction It has been suggested that transforming growth factor-β1 (TGF-β1) plays an important role in the pathogenesis of diabetes-induced erectile dysfunction. Aim To investigate the expression and activity of Smad transcriptional factors, the key molecules for the initiation of TGF-β-mediated fibrosis, in the penis of streptozotocin (STZ)-induced diabetic rats. Methods Fifty-two 8-week-old Sprague–Dawley rats were used and divided into control and diabetic groups. Diabetes was induced by an intravenous injection of STZ. Main Outcome Measures Eight weeks later, erectile function was measured by electrical stimulation of the cavernous nerve (N = 12 per group). The penis was harvested and stained with Masson trichrome or antibody to TGF-β1, phospho-Smad2 (P-Smad2), smooth muscle α-actin, and factor VIII (N = 12 per group). Penis specimens from a separate group of animals were used for TGF-β1 enzyme-linked immunosorbent assay (ELISA), P-Smad2/Smad2, phospho-Smad3 (P-Smad3)/Smad3, fibronectin, collagen I, and collagen IV western blot, or hydroxyproline determination. Results Erectile function was significantly reduced in diabetic rats compared with that in controls. The expression of TGF-β1, P-Smad2, and P-Smad3 protein evaluated by ELISA or western blot was higher in diabetic rats than in controls. Compared with that in control rats, P-Smad2 expression was higher mainly in smooth muscle cells and fibroblasts of diabetic rats, whereas no significant differences were noted in endothelial cells or in the dorsal nerve bundle. Cavernous smooth muscle and endothelial cell contents were lower in diabetic rats than in controls. Cavernous fibronectin, collagen IV, and hydroxyproline content was significantly higher in diabetic rats than in controls. Conclusion Upregulation of TGF-β1 and activation of the Smad signaling pathway in the penis of diabetic rats might play important roles in diabetes-induced structural changes and deterioration of erectile function.

Section: Discussionsupporting

confidence: 90%

“…The etiology of ED in diabetes is multifactorial. The proposed mechanisms of ED in diabetes include central or autonomic neuropathy, and functional or structural derangements of corpus cavernosum endothelial cells and smooth muscle cells, which are essential for penile erection [2][3][4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Role of Increased Penile Expression of Transforming Growth Factor-β1 and Activation of the Smad Signaling Pathway in Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats

Zhang

Piao

Choi

et al. 2008

“…Further structural changes associated with diabetes include the progressive loss of normal cavernosal endothelium and smooth muscle cells from corpus cavernosum [92] and increased collagen deposition and thickening of the basal lamina, leading to fibrosis [93].…”

Section: Peyronie's Disease Fibrosis Balanitis and Phimosismentioning

confidence: 99%

Erectile Dysfunction in Diabetes Mellitus

Malavige

Levy

2009

373

290

Introduction Type 2 diabetes is reaching pandemic levels and young-onset type 2 diabetes is becoming increasingly common. Erectile dysfunction (ED) is a common and distressing complication of diabetes. The pathophysiology and management of diabetic ED is significantly different to nondiabetic ED. Aim To provide an update on the epidemiology, risk factors, pathophysiology, and management of diabetic ED. Method Literature for this review was obtained from Medline and Embase searches and from relevant text books. Main Outcome Measures A comprehensive review on epidemiology, risk factors, pathophysiolgy, and management of diabetic ED. Results Large differences in the reported prevalence of ED from 35% to 90% among diabetic men could be due to differences in methodology and population characteristics. Advancing age, duration of diabetes, poor glycaemic control, hypertension, hyperlipidemia, sedentary lifestyle, smoking, and presence of other diabetic complications have been shown to be associated with diabetic ED in cross-sectional studies. Diabetic ED is multifactorial in aetiology and is more severe and more resistant to treatment compared with nondiabetic ED. Optimized glycaemic control, management of associated comorbidities and lifestyle modifications are essential in all patients. Psychosexual and relationship counseling would be beneficial for men with such coexisting problems. Hypogonadism, commonly found in diabetes, may need identification and treatment. Maximal doses of phosphodiesterase type 5 (PDE5) inhibitors are often needed. Transurethral prostaglandins, intracavenorsal injections, vacuum devices, and penile implants are the available therapeutic options for nonresponders to PDE5 inhibitors and for whom PDE5 inhibitors are contraindicated. Premature ejaculation and reduced libido are conditions commonly associated with diabetic ED and should be identified and treated. Conclusions Aetiology of diabetic ED is multifactorial although the relative significance of these factors are not clear. A holistic approach is needed in the management of diabetic ED.

“…Various animal models of vascular diseaseinduced ED have been developed to investigate the pathophysiologic mechanisms involved in the endothelial dysfunction resulting from hypercholesterolemia [5][6][7], type I diabetes [8][9][10], type II diabetes [11][12][13][14], and hypertension [15,16]. There is no doubt that these animal models have given us invaluable insight into the pathogenesis of vascular disease-induced endothelial dysfunction and subsequent ED.…”

Section: Introductionmentioning

confidence: 99%

Matrigel-Based Sprouting Endothelial Cell Culture System from Mouse Corpus Cavernosum is Potentially Useful for the Study of Endothelial and Erectile Dysfunction Related to High-Glucose Exposure

Yin

Kwon

Shin

et al. 2012

Introduction A proper cavernous endothelial cell culture system would be advantageous for the study of the pathophysiologic mechanisms involved in endothelial dysfunction and erectile dysfunction (ED). Aim To establish a nonenzymatic technique, which we termed the “Matrigel-based sprouting endothelial cell culture system,” for the isolation of mouse cavernous endothelial cells (MCECs) and an in vitro model that mimics in vivo situation for diabetes-induced ED. Methods For primary MCEC culture, mouse cavernous tissue was implanted into Matrigel and sprouting cells from the tissue were subcultivated. To establish an in vitro model for diabetes-induced ED, the primary cultured MCECs were exposed to a normal-glucose (5 mmoL) or a high-glucose (30 mmoL) condition for 48 hours. Main Outcome Measures The purity of isolated cells was determined by fluorescence-activated cell sorting analysis. MCECs incubated under the normal- or the high-glucose condition were used for Western blot, cyclic guanosine monophosphate (cGMP) quantification, and in vitro angiogenesis assay. Results We could consistently isolate high-purity MCECs (about 97%) with the Matrigel-based sprouting endothelial cell culture system. MCECs were subcultured up to the fifth passage and no significant changes were noted in endothelial cell morphology or purity. The phosphorylation of Akt and eNOS and the cGMP concentration were significantly lower in MCECs exposed to high glucose than in those exposed to normal glucose. MCECs exposed to the normal-glucose condition formed well-organized capillary-like structures, whereas derangements in tube formation were noted in MCECs exposed to high glucose. The protein expression of transforming growth factor-β1 (TGF-β1) and phospho-Smad2 was significantly increased by exposure to high glucose. Conclusion The Matrigel-based sprouting endothelial cell culture system is a simple, technically feasible, and reproducible technique for isolating pure cavernous endothelial cells in mice. An in vitro model for diabetic ED will be a valuable tool for evaluating the angiogenic potential of novel endogenous or synthetic modulators.