BMP2 restores erectile dysfunction through neurovascular regeneration and fibrosis reduction in diabetic mice

• Published in: Andrology (Oxford) 2024-02, Vol.12 (2), p.447-458
• Main Authors: Kwon, Mi‐Hye, Rho, Beom Yong, Choi, Min‐Ji, Limanjaya, Anita, Ock, Jiyeon, Yin, Guo Nan, Jin, Suk‐Won, Suh, Jun‐Kyu, Chung, Doo Yong, Ryu, Ji‐Kan
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; BMP2; Bone Morphogenetic Protein 2 - metabolism; Bone Morphogenetic Protein 2 - pharmacology; Collagen - metabolism; Collagen - pharmacology; Diabetes; Diabetes Mellitus, Experimental - complications; Disease Models, Animal; Endothelial Cells - metabolism; Erectile dysfunction; Erectile Dysfunction - drug therapy; Erectile Dysfunction - etiology; Erectile Dysfunction - metabolism; Glucose - metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Penile Erection; Penis; Phosphates - metabolism; Phosphates - pharmacology; Proteins; Streptozocin
• ISSN: 2047-2919; 2047-2927
• DOI: 10.1111/andr.13475

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 s