Chung DY, et al. Investig Clin Urol. 2023 Jul;64(4):312-324. https://doi.org/10.4111/icu.20230104

Penile erection requires well-coordinated interactions between vascular and nervous system. 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 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 co-culture system and ex vivo neurite sprouting assay, we found that DKK2-mediated juxtacrine signaling in pericyte-endothelial cell interactions promotes angiogenesis and neural regeneration though 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.

Yin GN. Investig Clin Urol. 2022 Jul;63(4):464-474. https://doi.org/10.4111/icu.20220038

Song KM, et al. World J Mens Health. 2019 Jan;37:e50. https://doi.org/10.5534/wjmh.190071

Kang DH, et al. World J Mens Health. 2018 Jan;36:e11. https://doi.org/10.5534/wjmh.170005