National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea.
Department of Anatomy, Kosin University College of Medicine, Busan, Korea.
Andrology. 2020 Sep;8(5):1387-1397. doi: 10.1111/andr.12784. Epub 2020 Apr 10.
Severe peripheral angiopathy in patients with diabetes is a major contributing factor for low response rate to phosphodiesterase-5 inhibitors.
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.
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 × 10 , 1 × 10 , 1 × 10 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.
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.
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.
糖尿病患者的外周血管严重病变是导致磷酸二酯酶-5 抑制剂反应率低的主要因素。
研究 Dickkopf3（DKK3）能否以及如何恢复糖尿病小鼠的勃起功能，DKK3 是 Wnt 通路的一种分泌调节剂，已知其参与内皮细胞修复和血管祖细胞迁移。
8 周龄 C57BL/6 小鼠腹腔注射链脲佐菌素（50mg/kg 共 5 天）。糖尿病诱导 8 周后，通过三个独立的实验来确定 DKK3 的疗效：实验 1（DKK3 肽[20μL PBS 中的 5μg]）；实验 2（DKK3 质粒 DNA 加电穿孔[20μL PBS 中分别为 10、40 或 100μg]）；实验 3（DKK3 腺病毒[20μL 中分别为 1×10 、1×10 、1×10 病毒颗粒]）。治疗后一周（肽）或两周（基因），通过电刺激海绵体神经测量勃起功能。体内检测 DKK3 在糖尿病阴茎中的血管生成活性和体外原代培养的小鼠海绵体内皮细胞（MCEC）中的活性。
糖尿病小鼠海绵体 DKK3 蛋白表达明显低于对照组。DKK3 肽或腺病毒显著改善糖尿病小鼠的勃起功能（达到对照组的 70%）。DKK3 腺病毒在体内显著恢复了糖尿病小鼠海绵体内皮细胞和周细胞的含量，并增加了内皮连接蛋白。DKK3 肽在体外高糖条件下培养的 MCEC 中诱导了血管生成因子（血管生成素-1、血管内皮生长因子和碱性成纤维细胞生长因子）的上调，并加速了管腔形成。
DKK3 恢复了糖尿病小鼠的海绵体血管完整性，改善了勃起功能。使用 DKK3 进行海绵体血管生成治疗将是治疗糖尿病性勃起功能障碍的一种有前途的治疗策略。
