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Background: The odds of erectile dysfunction are three times more prevalent in diabetes. Severe peripheral vascular and neural damage in diabetic patients responds poorly to phosphodiesterase‐5 (PDE5) inhibitors. However, bone morphogenetic protein 2 is known to be involved in angiogenesis. Objectives: To assess the efficacy of bone morphogenetic protein 2 in stimulating angiogenesis and augmenting nerve regeneration in a mouse model of diabetic‐induced erectile dysfunction. Materials and methods: The induction of diabetes mellitus was performed by streptozotocin (50 mg/kg daily) administered intraperitoneally for 5 successive days to male C57BL/6 mice that were 8 weeks old. Eight weeks post‐inductions, animals were allocated to one of five groups: a control group, a streptozotocin‐induced diabetic mouse group receiving two intracavernous 20 μL phosphate‐buffered saline injections, or one of three bone morphogenetic protein 2 groups administered two injections of bone morphogenetic protein 2 protein (1, 5, or 10 μg) diluted in 20 μL of phosphate‐buffered saline within a 3‐day interval between the first and second injections. The erectile functions were assessed 2 weeks after phosphate‐buffered saline or bone morphogenetic protein 2 protein injections by recording the intracavernous pressure through cavernous nerve electrical stimulation. Angiogenic activities and nerve regenerating effects of bone morphogenetic protein 2 were determined in penile tissues, aorta, vena cava, the main pelvic ganglions, the dorsal roots, and from the primary cultured mouse cavernous endothelial cells. Moreover, fibrosis‐related factor protein expressions were evaluated by western blotting. Results: Erectile function recovery to 81% of the control value in diabetic mice was found with intracavernous bone morphogenetic protein 2 injection (5 μg/20 μL). Pericytes and endothelial cells were extensively restored. It was confirmed that angiogenesis was promoted in the corpus cavernosum of diabetic mice treated with bone morphogenetic protein 2 through increased ex vivo sprouting of aortic rings, vena cava and penile tissues, and migration and tube formation of mouse cavernous endothelial cells. Bone morphogenetic protein 2 protein enhanced cell proliferation and reduced apoptosis in mouse cavernous endothelial cells and penile tissues, and promoted neurite outgrowth in major pelvic ganglia and dorsal root ganglia under high‐glucose conditions. Furthermore, bone morphogenetic protein 2 suppressed fibrosis by reducing mouse cavernous endothelial cell fibronectin, collagen 1, and collagen 4 levels under high‐glucose conditions. Conclusion: Bone morphogenetic protein 2 modulates neurovascular regeneration and inhibits fibrosis to revive the mouse erection function in diabetic conditions. Our findings propose that the bone morphogenetic protein 2 protein represents a novel and promising approach to treating diabetes‐related erectile dysfunction. [ABSTRACT FROM AUTHOR]

Background: Radical prostatectomy induces some degree of cavernous nerve injury (CNI) and causes denervation‐induced pathologic changes in cavernous vasculature, regardless of the advances in surgical techniques and robotic procedures. The precursor for nerve growth factor (proNGF) is known to be involved in neuronal cell apoptosis and microvascular dysfunction through its receptor p75NTR. Objectives: To determine the expression of proNGF/p75NTR and the efficacy of proNGF neutralizing antibody (anti‐proNGF‐Ab) in a mouse model of ED induced by CNI. Materials and Methods: Age‐matched 12‐week‐old C57BL/6 mice were distributed into three groups: sham group and bilateral CNI group treated with intracavernous injections of PBS (20 μL) or of anti‐proNGF‐Ab (20 µg in 20 μL of PBS) on days −3 and 0. Two weeks after treatment, erectile function was measured by electrical stimulation of cavernous nerve. Penis tissues from a separate group of animals were harvested for further analysis. We also determined the efficacy of anti‐proNGF‐Ab on neural preservation in major pelvic ganglion (MPG) ex vivo. Results: We observed increased penile expression of proNGF and p75NTR after CNI. Intracavernous administration of anti‐proNGF‐Ab increased nNOS and neurofilament expression probably by enhancing the production of neurotrophic factors, such as neurotrophin‐3, NGF, and brain‐derived neurotrophic factor. Anti‐proNGF‐Ab preserved the integrity of cavernous sinusoids, such as pericytes, endothelial cells, and endothelial cell‐to‐cell junctions, possibly by controlling angiogenic factors (angiopoietin‐1, angiopoietin‐2, and vascular endothelial growth factor) and induced endogenous eNOS phosphorylation in CNI mice. And finally, treatment with anti‐proNGF‐Ab rescued erectile function in CNI mice. Anti‐proNGF‐Ab also enhanced neurite sprouting from MPG exposed to lipopolysaccharide. Discussion and Conclusion: The preservation of damaged cavernous neurovasculature through inhibition of the proNGF/p75NTR pathway may be a novel strategy to treat radical prostatectomy‐induced erectile dysfunction. [ABSTRACT FROM AUTHOR]

Background: The incidence of diabetic erectile dysfunction (ED) is rapidly increasing, and due to the severe angiopathy caused by diabetes, current drugs are ineffective at treating ED. Insulin-like growth factor-binding protein 5 (IGFBP5) promotes cell death and induces apoptosis in various cell types., Objectives: To evaluate the effectiveness of IGFBP5 knockdown in improving erectile function in diabetic mice., Materials and Methods: Diabetes was induced by injecting streptozotocin (STZ) intraperitoneally into male 8-week-old C57BL/6 mice. Eight weeks after diabetes induction, mice were divided into four groups: a nondiabetic control group and three STZ-induced diabetic mice groups, which were administered intracavernous injections of phosphate buffered saline, scrambled control shRNA, or shRNA targeting mouse IGFBP5 (shIGFBP5) lentivirus particles. Two weeks later, we measured erectile function by electrically stimulating the bilateral cavernous nerve. To mimic diabetic angiopathy, primary cavernous endothelial cells (MCECs) from healthy mice were cultured and treated with glucose., Results: IGFBP5 expression in MCECs or cavernous tissues were significantly increased under diabetic conditions, and knockdown of IGFBP5 induced MCECs angiogenic activity under high-glucose conditions. STZ-induced diabetic mice had reduced erectile function, but shIGFBP5 treatment resulted in significant improvements (to 90% of the nondiabetic control group level). Furthermore, in diabetic mice, numbers of cavernous endothelial cells, pericytes, and neuronal cells were increased by shIGFBP5 treatment, which also increased eNOS Ser 1177 phosphorylation, decreased permeability and apoptosis of cavernous endothelial cells. In addition, IGFBP5 was found to mediate the AKT, ERK, p38 signaling pathways., Discussion and Conclusion: Knockdown of IGFBP5 improved erectile function in diabetic mice by promoting cell proliferation and reducing apoptosis and permeability. Local inhibition of IGFBP5 expression may provide a new treatment strategy for diabetic ED and other ischemic vascular or neurological diseases., (© 2022 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)