Erectile Function In Diabetic Rats Research Articles

Intracavernous Injection of Human Umbilical Cord Blood Mononuclear Cells Improves Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats

IntroductionErectile dysfunction (ED) worsens in men with diabetes. Human umbilical cord blood (HUCB), because of its widespread availability and low immunogenicity, is a valuable source for stem cell-based therapies. AimTo determine the effect of intracavernous injection of HUCB mononuclear cells (MNCs) on ED in rats with diabetes induced by streptozotocin. MethodsThirty adult male Sprague-Dawley rats were equally divided into three groups: (i) control, (ii) diabetes induced by streptozotocin (35 mg/kg intravenously for 8 weeks), and (iii) diabetic rats treated with MNCs (1 × 106 cells by intracavernosal injection). The HUCB-MNCs isolated by the Ficoll-Hypaque technique were obtained from eight healthy donors and administered to diabetic rats after 4 weeks. Main Outcome MeasuresThe ratio of intracavernosal pressure to mean arterial pressure ratio; the protein expression of endothelial and neuronal markers, such as von Willebrand factor, neuronal nitric oxide synthase, hypoxia-inducible factor-1α, and vascular endothelium growth factor; and the relative area of smooth muscle to collagen using western blotting and Masson trichrome staining were determined. ResultsDiabetic rats demonstrated a significantly decreased ratio of intracavernosal pressure to mean arterial pressure (0.26 ± 0.04; P < .01) and treatment with MNCs restored erectile function in diabetic rats (0.67 ± 0.05) compared with control rats (0.56 ± 0.02). In bath studies, neurogenic relaxant and contractile responses were significantly decreased in diabetic cavernosal tissues, which were restored by treatment. The ratio of smooth muscle to collagen was partly recovered by treatment, whereas von Willebrand factor levels were not altered in any group. Neuronal nitric oxide synthase and vascular endothelium growth factor levels were decreased, which were not restored by treatment. Increased hypoxia-inducible factor-1α protein expression in the diabetic group was completely normalized in MNC-treated diabetic samples. ConclusionThese results suggest that HUCB-MNC treatment can enhance the recovery of erectile function and promote numerous activities such the contribution of the hypoxia-inducible factor-1α and von Willebrand factor pathway to the neurogenic erectile response of diabetic rats. HUCB-MNCs in the healing process could involve an adaptive regenerative response and appear to be a potential candidate for cell-based therapy in ED of men with diabetes. It is evident that HUCB could provide a realistic therapeutic modality for the treatment of diabetic ED.

137 Superparamagnetic Iron Oxide Nanoparticle Targeting of Adipose Tissue-Derived Stem Cells in Diabetes-Associated Erectile Dysfunction

To explore the effect of Adipose tissue-derived stem cells (ADSCs) labelled with superparamagnetic iron oxide nanoparticles (SPIONs) on improving the erectile function of streptozocin (STZ)-induced diabetic rats with an external magnetic field. Ten-week-old male Sprague Dawley rats were injected either with STZ to induce diabetes or citrate buffer as controls. Rat ADSCs were harvested and labelled with SPIONs, and then transplanted into corpus cavernosum of STZ-induced diabetic rats with or without an external magnetic field. At 28 days after transplantation, all rats were sacrificed for tracking of transplanted cells. Erectile response was assessed by cavernous nerve stimulation. Smooth muscle, endothelium and vascular endothelial growth factor (VEGF) expression in corpora cavernosum were assessed using immunohistochemistry. In vitro studies revealed that stem cell properties were minimally affected by SPION labeling. With magnetic targeting, SPION-labelled ADSCs were visibly attracted toward the magnet field. In vivo experiments, magnetic targeting of ADSCs contributed to long-term cell retention in corpus cavernosum and improved the erectile function of diabetic rats compared with ADSC injection alone. ADSCs were identified in the corpus cavernosums of diabetic rats at 28 days after transplantation, and they were negative for vWF and a-SMA, indicating that ADSCs did not differentiate into endothelial or smooth muscle cells. VEGF expression in the corpus cavernosum was significantly increased in both ADSC-treated groups compared with the PBS-treated group. The underlying mechanism of recovery appears to the paracrine mechanism of transplanted ADSCs.

Effect of BKCa Channel Opener LDD175 on Erectile Function in an In Vivo Diabetic Rat Model

IntroductionThe development of novel therapeutic options is imperative in patients with erectile dysfunction, especially those non-responsive to phosphodiesterase type 5 inhibitors. LDD175, a potent BKCa channel opener, has a relaxation effect on the in vitro cavernosal smooth muscle strip. AimTo investigate the effect of LDD175 on erectile function using in vivo animal disease model. MethodsMale Sprague-Dawley rats were assigned to a normal control group and seven diabetic groups: diabetic control, sildenafil (1 and 5 mg/kg), LDD175 (5 and 10 mg/kg), LDD175 5 mg/kg plus sildenafil 1 mg/kg, and LDD175 10 mg/kg plus tetraethylammonium. Main Outcome MeasuresIntracavernosal pressure (ICP), ratio of ICP to mean arterial pressure (MAP), and the area under curve of ICP/MAP of eight groups were compared using in vivo pelvic nerve stimulation. ResultsThe ICP, ICP/MAP ratio, and area under curve of the ICP/MAP ratio of the normal control rats increased with an increase in electrical field stimulation voltage. All parameters in the diabetic control group were significantly lower than those in the normal control rats, with an electrical field stimulation ranging from 1 to 5 V (P < .05). LDD175 improved the erectile response in diabetic rats in a dose-dependent manner. The combination of sildenafil (1 mg/kg) and LDD175 (5 mg/kg) showed a significant additive effect (P < .05) on the improvement of erectile function compared with sildenafil (1 mg/kg) alone. The enhancement of erectile function by LDD175 was completely blocked by tetraethylammonium. ConclusionThe results showed that the BKCa channel opener LDD175 improved erectile function in an in vivo diabetic rat model. Furthermore, combination therapy of LDD175 and sildenafil had an additive effect on the improvement of erectile function in diabetic rats. LDD175 could be a new candidate for the treatment of erectile dysfunction.

Corrigendum to "Combination of low-energy shock-wave therapy and bone marrow mesenchymal stem cell transplantation to improve the erectile function of diabetic rats" by Hai-Tao Shan et al.

[This corrects the article DOI: 10.4103/1008-682X.184271.].

Effects of the start time of glycemic control on erectile function in streptozotocin-induced diabetic rats.

Diabetes-induced ED correlates with diabetes duration and glycemic control. This study evaluated the effect of glycemic control start time on erectile function in streptozotocin-induced diabetic rats. Rats were divided into normal controls (C); untreated diabetic rats (DM); and rats treated after 7 weeks (7W), and 10 weeks (10W) from DM. Treated diabetic rats received a timed daily injection of insulin. After 14 weeks of lab-controlled diabetes, experiments were performed. Group DM showed the ratio of intracavernosal pressure, significantly lower than other groups (10W vs DM; P<0.001). Groups 7W and 10W responded similarly, but did not recover to normal level (group C vs 7W; P<0.001). The percentage of α-smooth muscle actin increased more with earlier start times, and group DM's percentages decreased significantly (group 10W vs DM; P<0.001). Apoptosis recovered significantly only in group 7W, comparable to group C. As start times became earlier, for all molecules (eNOS, Akt, MYPT1 and PECAM-1), treatment groups' results neared those of group C. In conclusion, erectile function of diabetic rats recovered closer to normal controls if diabetic treatment started earlier. And the level of glycemic control was expected to be more important than the start time of diabetic treatment.

Combination of low-energy shock-wave therapy and bone marrow mesenchymal stem cell transplantation to improve the erectile function of diabetic rats.

Stem cell transplantation and low-energy shock-wave therapy (LESWT) have emerged as potential and effective treatment protocols for diabetic erectile dysfunction. During the tracking of transplanted stem cells in diabetic erectile dysfunction models, the number of visible stem cells was rather low and decreased quickly. LESWT could recruit endogenous stem cells to the cavernous body and improve the microenvironment in diabetic cavernous tissue. Thus, we deduced that LESWT might benefit transplanted stem cell survival and improve the effects of stem cell transplantation. In this research, 42 streptozotocin-induced diabetic rats were randomized into four groups: the diabetic group (n = 6), the LESWT group (n = 6), the bone marrow-derived mesenchymal stem cell (BMSC) transplantation group (n = 15), and the combination of LESWT and BMSC transplantation group (n = 15). One and three days after BMSC transplantation, three rats were randomly chosen to observe the survival numbers of BMSCs in the cavernous body. Four weeks after BMSC transplantation, the following parameters were assessed: the surviving number of transplanted BMSCs in the cavernous tissue, erectile function, real-time polymerase chain reaction, and penile immunohistochemical assessment. Our research found that LESWT favored the survival of transplanted BMSCs in the cavernous body, which might be related to increased stromal cell-derived factor-1 expression and the enhancement of angiogenesis in the diabetic cavernous tissue. The combination of LESWT and BMSC transplantation could improve the erectile function of diabetic erectile function rats more effectively than LESWT or BMSC transplantation performed alone.

Superparamagnetic iron oxide nanoparticle targeting of adipose tissue-derived stem cells in diabetes-associated erectile dysfunction.

Erectile dysfunction (ED) is a major complication of diabetes, and many diabetic men with ED are refractory to common ED therapies. Adipose tissue-derived stem cells (ADSCs) have been shown to improve erectile function in diabetic animal models. However, inadequate cell homing to damaged sites has limited their efficacy. Therefore, we explored the effect of ADSCs labeled with superparamagnetic iron oxide nanoparticles (SPIONs) on improving the erectile function of streptozotocin-induced diabetic rats with an external magnetic field. We found that SPIONs effectively incorporated into ADSCs and did not exert any negative effects on stem cell properties. Magnetic targeting of ADSCs contributed to long-term cell retention in the corpus cavernosum and improved the erectile function of diabetic rats compared with ADSC injection alone. In addition, the paracrine effect of ADSCs appeared to play the major role in functional and structural recovery. Accordingly, magnetic field-guided ADSC therapy is an effective approach for diabetes-associated ED therapy.

Stem Cell Therapy for Diabetic Erectile Dysfunction in Rats: A Meta-Analysis.

IntroductionStem cell therapy is a novel method for the treatment of diabetic erectile dysfunction (ED). Many relative animal studies have been done to evaluate the efficacy of this therapy in rats.AimsThis meta-analysis was performed to compare the efficacy of different stem cell therapies, to evaluate the influential factors and to determine the optimal stem cell therapeutic strategy for diabetic ED.MethodsWe searched the studies analyzing the efficacy of stem cell therapy for diabetic ED in rats published before September 30, 2015 in PubMed, Web of Science and EBSCO. A random effects meta-analysis was conducted to assess the outcomes of stem cell therapy. Subgroup analysis was also performed by separating these studies based on their different characteristics. Changes in the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP) and in the structure of the cavernous body were compared.Results10 studies with 302 rats were enrolled in this meta-analysis. Pooled analysis of these studies showed a beneficial effect of stem cell therapy in improving erectile function of diabetic rats (SMD 4.03, 95% CI = 3.22 to 4.84, P< 0.001). In the stem cell therapy group, both the smooth muscle and endothelium content were much more than those in control group. There was also significant increase in the expression of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS), the ratio of smooth muscle to collagen, as well as the secretion of vascular endothelial growth factor (VEGF). Besides, apoptotic cells were reduced by stem cell treatment. The subgroup analysis indicated that modified stem cells were more effective than those without modification.ConclusionsOur results confirmed that stem cell therapy could apparently improve the erectile function of diabetic rats. Some specific modification, especially the gene modification with growth factors, could improve the efficacy of stem cell therapy. Stem cell therapy has potential to be an effective therapeutic strategy for diabetic ED.

Low-intensity Pulsed Ultrasound Improves Erectile Function in Streptozotocin-induced Type I Diabetic Rats

To investigate the effect of low-intensity pulsed ultrasound (LIPUS) as a treatment for erectile dysfunction (ED) in a rat model of type I diabetes mellitus (DM) induced by streptozotocin (STZ). Seventy male Sprague-Dawley rats were randomly assigned to 2 cohorts: a normal control (NC) group and an STZ-induced DM group, which was further subdivided into DM, DM+LIPUS 100, DM+LIPUS 200, and DM+LIPUS 300 groups and a DM+LESWT (low-energy shock wave therapy) 300 positive control group. Animals in the LIPUS subgroups were treated at different energy levels (100, 200, and 300mW/cm(2)) for 3minutes, and animals in the LESWT group received 300 shocks at 0.09mJ/mm(2). All procedures were repeated 3 times per week for 2weeks. After a 2-week wash-out period, intracavernous pressure (ICP) was measured; the midpenile region was examined histologically; and VEGF, αSMA, eNOS, and nNOS expression, and activity of the TGF-β1/Smad/CTGF signaling pathway were examined in penile tissue by Western blot analysis. LIPUS therapy significantly improved erectile function in diabetic rats, as evidenced by enhanced ICP levels, increased endothelial and smooth muscle content, a higher collagen I/collagen III ratio, increased quantity of elastic fibers, and elevated eNOS and nNOS expression. Interestingly, LIPUS was also associated with downregulation of the TGF-β1/Smad/CTGF signaling pathway in penile tissue, whose activation is correlated with ED pathology. LIPUS therapy improved erectile function and reversed pathologic changes in penile tissue of STZ-induced diabetic rats. LIPUS therapy has potential as a noninvasive therapy for diabetic ED in the clinic.

Hepatocyte growth factor-modified adipose tissue-derived stem cells improve erectile function in streptozotocin-induced diabetic rats

TGFβ1-Smad signaling pathway is closely related to various tissues fibrosis. Hepatocyte growth factor (HGF) has been shown to antagonize TGFβ1-Smad signaling and may improve kidney tissue fibrosis in diabetic models. Penile fibrosis is a pathological condition which occurs during diabetic erectile dysfunction (ED). The aim of this study was to examine the effect of the treatment of ED in diabetic rats with a combination of HGF and adipose tissue-derived stem cells (ADSC). In this diabetes model, rats were injected intraperitoneally with 60 mg streptozotocin (STZ) to induce diabetes. Three months later, the diabetic rats were divided into a negative control(NC) group, an ADSC-treated group and an ADSC + HGF-treated group while normal rats were assigned into a sham group. Rats in the sham and NC groups were injected in the corpus cavernosum with phosphate-buffered saline, while rats in the other groups were injected with either ADSC or ADSC + HGF. One month later, erectile function was examined in each group and penile tissues were collected for experiments. The expression of smooth muscle actin (SMA) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) was analyzed by Western blotting. The smooth muscle and collagen deposition in corpus cavernosum was evaluated by Masson staining, while endothelial changes were assessed immunohistochemically. Cell apoptosis was detected by the TdT-mediated dUTP nick-end labeling (TUNEL) assay. The results revealed that ADSC alone can significantly improve erectile function in diabetic rats, but in combination with HGF the improvement was more prominent, showing higher content of smooth muscle and endothelial cells and lower cell apoptotic index in corpus cavernosum. Treatment with HGF can significantly enhance the beneficial effect of ADSC on erectile function in diabetic rats, and this effect might be closely related to the down-regulation of TGFβ1-Smad signaling.

A2B Adenosine Receptor Agonist Improves Erectile Function in Diabetic Rats.

Diabetes is an important risk factor for erectile dysfunction (ED). Recent studies have indicated that A2B adenosine receptor (ADORA2B) signaling is essential for penile erection. Thus, we hypothesize that diabetic ED may be attributed to impaired A2B adenosine signaling. To test this hypothesis, we generated diabetic rats by injecting streptozocin as animal model. After 12 weeks, immunohistochemistry staining was used to localize the expression of ADORA2B. Western Blot and quantitative PCR were employed to determine ADORA2B expression level. Intracavernosal pressure (ICP) measurement was used to evaluate erectile function. Diabetic rats received a single intravenous injection of BAY 60-6583, an ADORA2B agonist, or vehicle solution, at 60 min before the ICP measurement. The results showed that ADORA2B expressed in the nerve bundle, smooth muscle, and endothelium in penile tissue of control mice. Western Blot and quantitative PCR results indicated that the expression levels of ADORA2B protein and mRNA were significantly reduced in penile tissues of diabetic rats. Functional studies showed that the erectile response induced by electrical stimulation was remarkably decreased in diabetic rats, compared with age-matched control rats. However, at 60 min after BAY 60-6583 treatment, the erectile function was improved in diabetic rats, suggesting that enhancement of ADORA2B signaling may improve erectile function in diabetic ED. This preclinical study has revealed a previously unrecognized therapeutic possibility of BAY 60-6583 as an effective and mechanism-based drug to treat diabetic ED. In conclusion, we propose that impaired A2B adenosine signaling is one of the pathological mechanisms of diabetic ED.

Hydroxyl fasudil, an inhibitor of Rho signaling, improves erectile function in diabetic rats: a role for neuronal ROCK.

The pathogenesis of diabetic erectile dysfunction (ED) includes neuropathy, but the molecular basis for neurogenic ED is incompletely understood. The RhoA/ROCK pathway has been implicated in diabetic neuropathy and in ED, but its role in diabetic neurogenic ED is not known. The aim of this study was to determine whether hydroxyl fasudil, a ROCK inhibitor, affects diabetic neuropathy-related ED. Type 1 diabetes mellitus was induced in male rats by streptozotocin (75 mg/kg, intraperitoneally). After 8 weeks, diabetic rats were administered hydroxyl fasudil, a selective ROCK inhibitor (10 mg/kg/day, intraperitoneally) or vehicle, for 4 weeks. Age-matched control, nondiabetic, rats were treated intraperitoneally for 4 weeks with saline. At week 12, after a 2 day washout, neuro-stimulated erectile function was evaluated. Major pelvic ganglia (MPG) were collected for Western blot analysis of RhoA, ROCK-1, ROCK-2, phospho (P)-AKT (Ser(473) ), and P-phosphatase and tensin homolog (P-PTEN) (Ser(380) /Thr(382/383) ). Effect of ROCK inhibitor hydroxyl fasudil on erectile function and ROCK/P-AKT/P-PTEN pathway in the MPG of diabetic rats. Erectile response was significantly (P < 0.05) reduced in diabetic rats compared with nondiabetic rats and was preserved (P < 0.05) in diabetic rats treated with hydroxyl fasudil. In diabetic rats, RhoA and ROCK-2 protein expressions in MPG were increased (P < 0.05) and remained increased in hydroxyl fasudil-treated rats. P-AKT (Ser(473) ) expression was decreased (P < 0.05), whereas P-PTEN (Ser(380) /Thr(382/383) ) expression was increased (P < 0.05) in MPG of diabetic rats compared with nondiabetic rats, and both were reversed (P < 0.05) in diabetic rats treated with hydroxyl fasudil. Improved erectile function and restored P-AKT and P-PTEN in the MPG with hydroxyl fasudil treatment suggest the role of Rho signaling via PTEN/AKT pathway in neurogenic diabetic ED.

AB178. Apocynin improves erectile function indiabetic rats through regulation of NADPH oxidase expression

IntroductionDiabetes is a risk factor for erectile dysfunction (ED). The proposed mechanisms responsible fordiabetic ED are associated with an increase in reactive oxygen species (ROS) production, over activity of RhoA/ROCK signaling pathway and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, as seen in experimental models of diabetic rats.AimThe aim of this study was to investigate whether NADPH oxidase inhibitor apocynin can ameliorate streptozotocin (STZ)-induced diabetes-related ED by reducing the ROS production and inhibiting the activity of RhoA/ROCK signaling pathway.MethodsThe diabetic rats were treated with and without the NADPH oxidase inhibitor apocynin.Main outcome measuresErectile responses were evaluated by determining mean arterial blood pressure (MAP) and intracavernosal pressure (ICP) with electrical stimulation of the cavernous nerve. Levels of mRNA expression were measured by real-time polymerase chain reaction (RT-PCR). Levels of protein expression were examined by Western Blot. ROS production was measured by dihydroethidium (DHE) staining and thiobarbituric acid reactive substances assay.ResultsThe ratio of maximum ICP-to-MAP (max ICP/MAP) was significantly decreased in diabetic ED rats, compared to that of age-matched control rats (P<0.05). Apocynin improved erectile function of diabetic rats (P<0.05). Expression levels of RhoA (cytosol), nNOS and eNOS were reduced, compared to those of control rats (P<0.05). Apocynin significantly elevated their expression levels in diabetic rats (P<0.05). Expression levels of ROCK1, RhoA (membrane fraction), p-MYPT1 and NADPH oxidase subunits p47 (phox) and p67 (phox) were increased in diabetic rats when compared to those of control rats (P<0.05), and it was observed that apocynin significantly reduced their expression levels in diabetic rats (P<0.05). ROS production was increased in diabetic rats when compared to that of control rats (P<0.05), the effect of apocynin was a reduction in the ROS production in diabetic rats (P<0.05).

MP43-12 INHIBITION OF PHOSPHODIESTERASE-5 IMPROVES THERAPEUTIC EFFICACY OF ADIPOSE-DERIVED STEM CELLS FOR ERECTILE DYSFUNCTION IN DIABETIC RATS

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research I1 Apr 2014MP43-12 INHIBITION OF PHOSPHODIESTERASE-5 IMPROVES THERAPEUTIC EFFICACY OF ADIPOSE-DERIVED STEM CELLS FOR ERECTILE DYSFUNCTION IN DIABETIC RATS Jun Yang, Tao Wang, Yan Zhang, Li Zhuan, Hua Xu, Shao-Gang Wang, Ji-Hong Liu, and Zhang-Qun Ye Jun YangJun Yang More articles by this author , Tao WangTao Wang More articles by this author , Yan ZhangYan Zhang More articles by this author , Li ZhuanLi Zhuan More articles by this author , Hua XuHua Xu More articles by this author , Shao-Gang WangShao-Gang Wang More articles by this author , Ji-Hong LiuJi-Hong Liu More articles by this author , and Zhang-Qun YeZhang-Qun Ye More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1169AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Adipsoe-derived stem cells (ADSCs) have been recently considered promising therapy for erectile dysfunction (ED). However, the therapeutic efficacy of ADSCs-based therapy remains to be improved. This study was designed to determine whether inhibition of phosphodiesterase-5 (PDE5) with a silencing vector in adipose-derived stem cells (ADSCs) would improve stem cell therapy for erectile dysfunction in diabetic rats, and to investigate its underlying mechanisms. Methods A PDE5 siRNA was incorporated into lentiviral vectors and then transduced into ADSCs. Cells were evaluated for PDE5 mRNA and protein expression, and cGMP level at different time points. 3 days after transduction, the ADSCs-conditioned medium was collected to determinate the level of IGF-1 and VEGF. A streptozotocin-induced diabetes rat model was established and used for comparative analysis of 2-week treatment regimens with ADSCs or PDE5 siRNA modified ADSCs. At 2-week post-transplantation, all the rats were analyzed for erectile function, cavernous IGF-1 and VEGF levels, and penile histology. Results Compared to ADSCs transfected with negative control siRNA vector (ADSCs plus vector), ADSCs showed a significant decrease in PDE5 expression and elevated cGMP level at 3d, 5d, 7d, 10d and 14d after transfection with PDE5 siRNA vector (ADSCs plus siRNA) (P<0.05). ADSCs plus siRNA could secrete more IGF-1 and VEGF in culture medium than those of ADSCs and ADSCs plus vector (P<0.05). Compared to normal control rats (2.5v 0.711±0.059, n=10), the Max ICP/MAP was found to be markedly decreased in untreated diabetic rats (2.5v 0.355±0.046, n=10) (P<0.05). The corpus cavernosum of untreated diabetic rats showed decreased IGF-1 and VEGF levels, and contents of cavernous smooth muscle and endothelium compared to normal control rats (P<0.05). Diabetic rats injected with ADSCs plus siRNA (2.5v 0.665±0.052, n=10) showed enhanced erectile function as compared to ADSCs (2.5v 0.522±0.043, n=10) or ADSCs plus vector (2.5v 0.515±0.038, n=10) treatment (P<0.05), which also improved erectile function of diabetic rats (P<0.05). The benefits of ADSCs plus siRNA therapy were associated with significantly increased IGF-1 and VEGF levels, and contents of cavernous smooth muscle and endothelium in penile tissues as compared with ADSCs or ADSCs plus vector treatment (P<0.05). Conclusions Inhibition of PDE5 can be a powerful approach to improve stem cell therapy for erectile dysfunction in diabetic rats. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e481 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Jun Yang More articles by this author Tao Wang More articles by this author Yan Zhang More articles by this author Li Zhuan More articles by this author Hua Xu More articles by this author Shao-Gang Wang More articles by this author Ji-Hong Liu More articles by this author Zhang-Qun Ye More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Myocardin restores erectile function in diabetic rats: phenotypic modulation of corpus cavernosum smooth muscle cells

This study aimed to investigate whether gene transfer of myocardin to the penis of diabetic rats can modulate corpus cavernosum smooth muscle (CCSM) cells phenotype and restore erectile function. Five normal control rats, and 22 diabetic rats were randomly divided into four groups: rats transfected with adCMV-myocardin (N=6), treated with empty vector (N=6), injected with medium (N=5), and sham-operated rats (N=5). The erectile response was measured 7days after transfection. The percent of smooth muscle and the expressions of SMα-actin, smooth muscle myosin heavy chain (SMMHC), calponin were evaluated. The increases in intracorporal pressure(ICP)/mean arterial pressure and total ICP in response to nerve stimulation in the adCMV-myocardin treated rats were significantly greater than those in the empty vector (P<0.001 and P<0.001), medium only (P<0.001 and P<0.001), and sham-operated rats (P<0.001 and P<0.001). The suppressed expressions of SMα-actin, SMMHC and calponin were completely restored, and the amount of smooth muscle in diabetic rats were not restored after treatment. It is concluded that myocardin ameliorated erectile responses in diabetic rats mainly via promoting phenotypic modulation of CCSM cells from a proliferative to a contractile state.

Panax notoginseng Saponins Improve Erectile Function through Attenuation of Oxidative Stress, Restoration of Akt Activity and Protection of Endothelial and Smooth Muscle Cells in Diabetic Rats with Erectile Dysfunction

Panax notoginseng saponins (PNS), which have an antioxidant property, are a widely used traditional Chinese medicine. In this study we investigated whether PNS can improve erectile function in rats with erectile dysfunction and the underlying mechanism by using a rat diabetic erectile dysfunction model. The rats were randomly divided into four groups: three PNS-treated groups (50, 100 and 150 mg/kg) and one saline-treated control group. Four weeks post treatment, electrostimulation was applied to the cavernous nerve and intracavernous pressure was measured to assess erectile function. Malondialdehyde, superoxide dismutase and glutathione were detected in the penises of all rats. Ultrastructural changes in the penises were examined by electron microscopy. Expression of Akt was detected by immunohistochemistry. The results showed that intracavernous pressure was increased in PNS-treated groups (100 and 150 mg/kg) compared to the control group. The levels of superoxide dismutase, glutathione and Akt were increased (p < 0.05) while that of malondialdehyde was decreased in the PNS groups. Ruptured endothelium, impaired smooth muscle cells and thrombus in the penises were detected by electron microscopy in the control group, but not in the PNS groups (10 and 150 mg/kg). The results suggest that PNS improves erectile function in diabetic rats. This improvement was associated with increased Akt expression, suppressed oxidative stress and restored functions of endothelial cells and smooth muscle cells in the penis.

SaRNA Guided iNOS Up-Regulation Improves Erectile Function of Diabetic Rats

saRNA Guided iNOS Up-Regulation Improves Erectile Function of Diabetic Rats

Correction of diabetic erectile dysfunction with adipose derived stem cells modified with the vascular endothelial growth factor gene in a rodent diabetic model.

The aim of this study was to determine whether adipose derived stem cells (ADSCs) expressing vascular endothelial growth factor (VEGF) gene can improve endothelial function, recover the impaired VEGF signaling pathway and enhance smooth muscle contents in a rat diabetic erectile dysfunction (DED) model. DED rats were induced via intraperitoneal injection of streptozotocin (40 mg/kg), and then screened by apomorphine (100 µg/kg). Five groups were used (n = 12/group)–Group 1 (G1): intracavernous injection of lentivirus-VEGF; G2: ADSCs injection; G3: VEGF-expressing ADSCs injection; G4: Phosphate buffered saline injection; G1–G4 were DED rats; G5: normal rats. The mean arterial pressure (MAP) and intracavernosal pressure (ICP) were measured at days 7 and 28 after the injections. The components of the VEGF system, endothelial, smooth muscle, pericytes markers in cavernoursal tissue were assessed. On day 28 after injection, the group with intracavernosum injection of ADSCs expressing VEGF displayed more efficiently and significantly raised ICP and ICP/MAP (p<0.01) than those with ADSCs or lentivirus-VEGF injection. Western blot and immunofluorescent analysis demonstrated that improved erectile function by ADSCs-VEGF was associated with increased expression of endothelial markers (VEGF, VEGF R1, VEGF R2, eNOS, CD31 and vWF), smooth muscle markers (a-actin and smoothelin), and pericyte markers (CD146 and NG2). ADSCs expressing VEGF produced a therapeutic effect and restored erectile function in diabetic rats by enhancing VEGF-stimulated endothelial function and increasing the contents of smooth muscle and pericytes.

Adrenomedullin and Angiopoietin-1 Additively Restore Erectile Function in Diabetic Rats: Comparison with the Combination Therapy of Vascular Endothelial Growth Factor and Angiopoietin-1

Erectile dysfunction (ED) is a major health problem. We have shown that adrenomedullin (AM) restores erectile function in diabetic rats. The aim of this study is to explore a better treatment for ED, we examined whether combination of AM and angiopoietin-1 (Ang-1) was more effective to treat ED than treatment with AM alone or Ang-1 alone. We also compared the effect of the combination therapy with that of treatment with vascular endothelial growth factor-A (VEGF-A). Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. Adenoviruses expressing AM (AdAM), Ang-1 (AdAng-1), and VEGF-A (AdVEGF-A) were injected into the penis 6 weeks after STZ administration. Erectile function, penile histology, and protein expression were analyzed 4 weeks after the injection of the adenoviruses. Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. The morphology of the penis was analyzed by Elastica van Gieson stain and immunohistochemistry. The expression of α-smooth muscle actin (SMA), VE-cadherin and type I collagen was assessed by Western blot analysis. Infection with AdAM plus AdAng-1 more effectively restored erectile function than infection with AdAM alone or AdAng-1 alone. This combination therapy restored erectile function to a level similar to that observed in the age-matched Wistar rats. Expression of SMA and VE-cadherin increased more significantly in the AdAM plus AdAng-1-treated group than in the AdAM- or AdAng-1-treated group. Although AdVEGF-A infection restored erectile function significantly, it also caused enlargement of the trabeculae of the cavernous body, aberrant angiogenesis, and overproduction of type I collagen. These results suggested that combination therapy with AM and Ang-1 potently restored erectile function and normal morphology of the cavernous body compared with VEGF-A administration. This combination therapy will be useful to treat ED patients with a severely damaged cavernous body.

Evaluation of the Effect of Different Doses of Low Energy Shock Wave Therapy on the Erectile Function of Streptozotocin (STZ)-Induced Diabetic Rats

To investigate the therapeutic effect of different doses of low energy shock wave therapy (LESWT) on the erectile dysfunction (ED) in streptozotocin (STZ) induced diabetic rats. SD rats (n = 75) were randomly divided into 5 groups (normal control, diabetic control, 3 different dose LESWT treated diabetic groups). Diabetic rats were induced by intra-peritoneal injection of STZ (60 mg/kg) and rats with fasting blood glucose ≥ 300 mg/dL were selected as diabetic models. Twelve weeks later, different doses of LESWT (100, 200 and 300 shocks each time) treatment on penises were used to treat ED (7.33 MPa, 2 shocks/s) three times a week for two weeks. The erectile function was evaluated by intracavernous pressure (ICP) after 1 week washout period. Then the penises were harvested for histological study. The results showed LESWT could significantly improve the erectile function of diabetic rats, increase smooth muscle and endothelial contents, up-regulate the expression of α-SMA, vWF, nNOS and VEGF, and down- regulate the expression of RAGE in corpus cavernosum. The therapeutic effect might relate to treatment dose positively, and the maximal therapeutic effect was noted in the LESWT300 group. Consequently, 300 shocks each time might be the ideal LESWT dose for diabetic ED treatment.