Bone morphogenetic protein 2 rescues neurogenic abnormalities and angiogenic factors in mice with bilateral cavernous nerve injury

Abstract

Background Bone morphogenetic protein 2 (BMP2), a key isoform within the bone morphogenetic protein family, plays a critical role in promoting angiogenesis and peripheral nerve regeneration, but its specific role in neurogenic erectile dysfunction (ED) remains unclear.Aim This study aimed to explore the therapeutic efficacy of exogenous recombinant BMP2 protein administration in restoring erectile function in a mouse model of cavernous nerve injury (CNI)-induced ED.Methods Twelve-week-old male C57BL/6 mice were used to evaluate BMP2 expression and erectile function following CNI. Western blotting and immunofluorescence staining were employed to assess BMP2 levels in corpus cavernosum tissues from both sham-operated and CNI-induced ED mice. Erectile function was measured through electrical stimulation of bilateral cavernous nerves, with subsequent intracavernous pressure parameter recordings. Mechanistic investigations included immunofluorescence staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and western blot analysis. Additionally, ex vivo neurite outgrowth assays were conducted using dorsal root ganglia (DRG) and major pelvic ganglia (MPG) tissues.Outcomes In vivo intracavernous pressure, neurovascular regeneration, proliferation, apoptosis, ex vivo neurite sprouting, and survival signaling were measured.Results Bone morphogenetic protein 2 expression was significantly decreased in the corpus cavernosum of CNI mice. Exogenous administration of recombinant BMP2 protein effectively enhanced erectile function in CNI mice, likely through the restoration of endothelial cells, smooth muscle cells, pericytes, and neuronal cells within the corpus cavernosum. Immunofluorescence staining and western blot analysis demonstrated that BMP2 treatment promoted angiogenesis by increasing endothelial cell proliferation and reducing apoptosis in the corpus cavernosum. Furthermore, ex vivo assays revealed that BMP2 promoted neurite sprouting in DRG and MPG tissues exposed to lipopolysaccharide. Mechanistic studies further indicated that BMP2 increased the expression of neurotrophic factors and VEGF, activating the AKT/eNOS signaling pathway.Clinical Implications Bone morphogenetic protein 2 may be used as a strategy to treat neurogenic ED or other neurovascular diseases.Strengths and Limitations Bone morphogenetic protein 2 has dual roles in vascular and neuronal development. Our study focused on broadly evaluating the role of BMP2 in neurogenic ED. Future studies will evaluate the nerve regeneration effects and novel signaling pathways of BMP2 in a sciatic nerve injury mouse model. In view of its properties as an angiogenic factor, its dose concentration should be strictly controlled to avoid potential side effects.Conclusions The exogenous administration of recombinant BMP2 protein significantly improved erectile function in CNI mice, suggesting BMP2 as a promising therapeutic candidate for neurogenic ED.