Intracavernous delivery of Dickkopf3 gene or peptide rescues erectile function through enhanced cavernous angiogenesis in the diabetic mouse

Abstract

Background Severe peripheral angiopathy in patients with diabetes is a major contributing factor for low response rate to phosphodiesterase‐5 inhibitors. Objectives To examine whether and how Dickkopf3 (DKK3), a secreted modulator of the Wnt pathway that known to be involved in endothelial cell repair and vascular progenitor cell migration, restores erectile function in diabetic mice. Methods Eight‐week‐old C57BL/6 mice received intraperitoneal injections of streptozotocin (50 mg/kg for 5 days). Eight weeks after the diabetes was induced, the efficacy of DKK3 was determined by three independent experiments: experiment 1 (DKK3 peptide [5 μg in 20 μL PBS]); experiment 2 (DKK3 plasmid DNA with electroporation [10, 40, or 100 μg in 20 μL PBS, respectively]); and experiment 3 (DKK3 adenovirus [1 × 107, 1 × 108, 1 × 109 virus particles per 20 μL, respectively]). Erectile function was measured by electrical stimulation of the cavernous nerve one week (for peptide) or two weeks (for genes) after treatment. The angiogenic activity of DKK3 was determined in diabetic penis in vivo and in primary cultured mouse cavernous endothelial cells (MCECs) in vitro. Results The cavernous expression of DKK3 protein was significantly lower in the diabetic mice than in controls. DKK3 peptide or adenovirus significantly improved erectile function in diabetic mice (70% of the control values). DKK3 adenovirus profoundly restored cavernous endothelial cell and pericyte contents and increased endothelial junction proteins in diabetic mice in vivo. DKK3 peptide induced upregulation of angiogenic factors (angiopoietin‐1, vascular endothelial growth factor, and basic fibroblast growth factor) and accelerated tube formation in MCECs cultivated under the high‐glucose condition in vitro. Conclusion DKK3 restored cavernous vascular integrity and improved erectile function in diabetic mice. Therapeutic cavernous angiogenesis by the use of DKK3 will be a promising therapeutic strategy to treat diabetic erectile dysfunction.

Short Sleep Duration and Erectile Dysfunction: A Review of the Literature

“… 149 Meanwhile, the inhibition of Wnt signaling via Dickkopf3 (DKK3) could improve the erectile function in diabetic models through restoring the cavernous vascular integrity and endothelial function. 150 Hence, the Wnt pathway may represent a potential target in the management of ED.…”

Role of Pericytes in Diabetic Angiogenesis

“…54 However, for diabetic patients, insulin cannot prevent the deterioration of erectile function, and the effects of anti-ED drug phosphodiesterase-5 inhibitors are not satisfactory. 54,72 DKK2 (Dickkopf-2) is a type of Wnt antagonist that is mainly expressed in pericytes. 54 After being transferred to ECs, DKK2 relies on the Ang-1-Tie-2 signaling pathway to promote angiogenesis.…”

“…54 In diabetes, the number of pericytes decreases, and the expression of DKK2 also decreases. 54,72 Overexpression of DKK2 in a diabetic environment can reduce ROS, activate pericytes to regenerate blood vessels, protect neurotrophic function, and restore the erectile function of the penis. 54 DKK2, with dual angiogenetic and neurotrophic effects, is a new target for the treatment of diabetic ED.…”

“…72 Among them, adenoviruses expressing the DKK3 gene can significantly increase the number of pericytes and ECs, although the mechanism remains unclear. 72…”

The role of microRNAs in erectile dysfunction: From pathogenesis to therapeutic potential

“…Damage to the vascular endothelium can lead to vascular dysfunction, which in turn can cause ED. In contrast, the use of vascular growth factors to promote revascularization can effectively improve ED ( 101 , 102 ). RNA sequencing data from Ouyang et al.…”