Objective-Tremendous efforts have been made to establish effective therapeutic neovascularization using adipose tissue-derived stromal vascular fraction (SVF), but the efficiency is low, and underlying mechanisms and their interaction with the host in a new microenvironment are poorly understood. Methods and Results-Here we demonstrate that direct implantation of SVF derived from donor adipose tissue can create a profound vascular network through the disassembly and reassembly of blood endothelial cells at the site of implantation. This neovasculature successfully established connection with recipient blood vessels to form a functionally perfused circuit. Addition of vascular growth factors to the SVF implant improved the efficiency of functional neovasculature formation. In contrast, spheroid culture of SVF before implantation reduced the capacity of vasculature formation, possibly because of cellular alteration. Implanting SVF into the mouse ischemic hindlimb induced the robust formation of a local neovascular network and salvaged the limb. Moreover, the coimplantation of SVF prevented fat absorption in the subcutaneous adipose tissue graft model. Conclusion-Freshly isolated SVF can effectively induce new vessel formation through the dynamic reassembly of blood endothelial cells and could be applied to achieve therapeutic neovascularization for relieving ischemia and preventing fat absorption in an autologous manner.

Introduction Udenafil is a potent selective phosphodiesterase type 5 (PDE5) inhibitor newly developed for the treatment of erectile dysfunction (ED). Aim This study was performed to evaluate the efficacy and safety of udenafil therapy in patients with ED. Methods In this multicenter, double-blind, placebo-controlled, fixed-dose, parallel-group phase III trial, 167 patients with ED of diverse origin and severity were randomized to take placebo or udenafil at fixed doses of 100 or 200 mg as needed for 12 weeks. Main Outcome Measures Primary efficacy variable was change from baseline in erectile function (EF) domain scores of the International Index of Erectile Dysfunction (IIEF) questionnaire. Secondary efficacy variables include change from baseline in scores on the IIEF Questions 3 and 4 (IIEF Q3 and Q4), change from baseline in all domain scores of the IIEF, patients' responses to questions 2 and 3 of the Sexual Encounter Profile (SEP2 and SEP3), and patients' responses to the Global Assessment Question (GAQ). Any adverse events were also recorded during the trial. Results After 12 weeks of treatment, the patients treated with udenafil showed significantly greater change from baseline in the IIEF-EF domain score compared with placebo (placebo, 0.20; 100-mg udenafil, 7.52; and 200-mg udenafil, 9.93, respectively) (P <0.0001). Compared with placebo, udenafil significantly enhanced the rates of successful penetration (SEP Q2) and maintenance of erection (SEP Q3) (P <0.0001). Furthermore, significantly greater proportions of udenafil treatment groups responded positively to the GAQ compared with the placebo group (GAQ: placebo, 25.9%; 100-mg udenafil, 81.5%; and 200-mg udenafil, 88.5%, respectively) (P <0.0001). Treatment-related adverse events were generally mild to moderate with facial flushing and headache being the most common. Conclusions Udenafil is an effective and well-tolerated therapy for ED of broad-spectrum etiology and severity.

Hypercholesterolemia-related endothelial cell dysfunction and decreased endothelium-derived nitric oxide formation may account for impaired angiogenesis and subsequent erectile dysfunction. Angiopoietin-1 (Ang1) is a critical angiogenic factor for vascular maturation and enhances vascular endothelial growth factor (VEGF)-induced angiogenesis in a complementary manner. We hypothesized that combined adenovirus-delivered human Ang1 (ad-Ang1) and VEGF165 (ad-VEGF165) gene transfer might promote angiogenesis cooperatively in a rat model of hypercholesterolemic erectile dysfunction and result in a recovery of erectile function. Ad-Ang1 and ad-VEGF165 were injected either alone or in combination into the corpus cavernosum of the penis. Combined gene transfer of both ad-Ang1 and ad-VEGF165 significantly increased cavernous angiogenesis, eNOS phosphorylation, and cGMP expression compared with that in the groups treated with either therapy alone. Erectile function, as evaluated by electrical stimulation of the cavernous nerve 2 and 8 weeks after treatment, was completely restored in the combined treatment group, whereas intracavernous injection of either ad-Ang1 or ad-VEGF165 alone elicited partial improvement. The results indicate that combined application of angiogenic factors may enhance cavernous angiogenesis cooperatively by reinforcing the endothelium both structurally and functionally, which results in an additive effect on erectile function in hypercholesterolemic rats.

Introduction Mirodenafil is a recently developed oral phosphodiesterase type 5 inhibitor, which was observed to significantly improve erectile function and was well tolerated in men with broad-spectrum erectile dysfunction (ED). Aim To investigate the efficacy and safety of mirodenafil treatment compared with placebo in men taking at least one antihypertensive medication. Methods A multicenter, double-blind, placebo-controlled, parallel group, fixed-dose study was conducted with 109 subjects who were randomized to placebo or mirodenafil 100 mg for 12 weeks on an “as needed” basis. Main Outcome Measures The primary efficacy measures were the changes from baseline in sum of scores on International Index of Erectile Function-erectile function domain (IIEF-EF) questions 1 to 5 and 15 with treatment. The secondary efficacy measures included scores on IIEF question 3 and 4 (Q3 and Q4), all domain scores of IIEF, and Sexual Encounter Profile Question 2 and 3 (SEP2 and SEP3) along with responses to Global Assessment Question (GAQ) and Life Satisfaction Checklist (LSC). The safety assessments included laboratory tests, vital signs, 12-lead electrocardiogram recordings, and patients’ reporting of adverse events. Results The mirodenafil group showed significantly greater increase in IIEF-EF scores at 12 weeks compared with the placebo group (9.35 ± 6.86 vs. 2.66 ± 6.44, P <0.001). The mirodenafil group also demonstrated significantly greater improvement in scores of IIEF Q3 and Q4, other four domains of IIEF, SEP2, SEP3, and LSC along with percentages of patients responding positively to GAQ compared with the placebo group. During the study, no clinically significant changes were observed regarding blood pressure, heart rate, electrocardiographic findings, or laboratory values. Facial flushing and headache were the most common treatment-associated adverse events, which were mild or moderate in severity, resolving spontaneously. Conclusions Mirodenafil was effective and safe in men with ED concomitantly taking antihypertensive medications.

Penile erection requires well-coordinated interactions between vascular and nervous systems. Penile neurovascular dysfunction is a major cause of erectile dysfunction (ED) in patients with diabetes, which causes poor response to oral phosphodiesterase-5 inhibitors. Dickkopf2 (DKK2), a Wnt antagonist, is known to promote angiogenesis. Here, using DKK2-Tg mice or DKK2 protein administration, we demonstrate that the overexpression of DKK2 in diabetic mice enhances penile angiogenesis and neural regeneration and restores erectile function. Transcriptome analysis revealed that angiopoietin-1 and angiopoietin-2 are target genes for DKK2. Using an endothelial cell-pericyte coculture system and ex vivo neurite sprouting assay, we found that DKK2-mediated juxtacrine signaling in pericyte-endothelial cell interactions promotes angiogenesis and neural regeneration through an angiopoietin-1-Tie2 pathway, rescuing erectile function in diabetic mice. The dual angiogenic and neurotrophic effects of DKK2, especially as a therapeutic protein, will open new avenues to treating diabetic ED.