背景:肝素结合表皮生长因子样生长因子(HB-EGF)是一种促血管生成因子;然而,据我们所知,目前尚无关于HB-EGF与糖尿病性勃起功能障碍(ED)之间关系的报道。
目的:本研究旨在确定HB-EGF是否能改善链脲佐菌素诱导的糖尿病小鼠的勃起功能并探讨相关机制。
方法:将8周龄雄性C57BL/6小鼠用于糖尿病诱导。连续5天低剂量注射链脲佐菌素(50mg/kg)可诱发糖尿病(DM)。注射链脲佐菌素八周后,通过测量血糖和体重来确定DM。糖尿病小鼠用两次海绵体内施用磷酸盐缓冲盐水(20μL)或各种剂量的HB-EGF(第-3天和0天;在20μL磷酸盐缓冲盐水中的1、5和10μg)治疗。在高糖条件下,通过在小鼠海绵状内皮细胞和小鼠海绵状周细胞中的管形成和迁移测定证实了HB-EGF的血管生成作用。通过电刺激海绵状神经测量勃起功能,以及组织学检查和蛋白质印迹分析进行机制评估。
结果:体外血管生成,细胞增殖,体内海绵体内压,神经血管再生,海绵状渗透性,和生存信号是测量的结果。
结果:在糖尿病状态下HB-EGF的表达降低。在高糖条件下,外源性HB-EGF在小鼠海绵状内皮细胞和小鼠海绵状周细胞中诱导血管生成。DM组勃起功能下降,而HB-EGF的给药导致勃起功能的显着改善(年龄匹配的对照组的91%)与神经血管含量的增加有关,包括海绵状内皮细胞,周细胞,和神经元细胞。组织学和蛋白质印迹分析显示DM小鼠海绵体通透性显著增加,通过HB-EGF处理减毒。HB-EGF治疗后,磷酸化-AktSer473和磷酸化内皮一氧化氮合酶Ser1177的蛋白表达增加。
结论:使用HB-EGF可能是治疗与DM或其他神经血管疾病相关的ED的有效策略。
■与其他促血管生成因子相似,HB-EGF在血管和神经元发育中具有双重作用。我们的研究集中在广泛评估HB-EGF在糖尿病性ED中的作用。鉴于HB-EGF作为血管生成因子的特性,应严格控制其剂量浓度,以避免潜在的副作用。
结论:在本研究的糖尿病ED小鼠模型中,HB-EGF改善了勃起功能,这可能为对磷酸二酯酶5抑制剂无反应的ED患者提供新的治疗策略。
BACKGROUND: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) serves as a pro-angiogenic factor; however, there is to our knowledge currently no reported research on the relationship between HB-EGF and diabetic erectile dysfunction (ED).
OBJECTIVE: In this study we aimed to determine whether HB-EGF can improve the erectile function of streptozotocin-induced diabetic mice and to explore the related mechanisms.
METHODS: Eight-week-old male C57BL/6 mice were used for diabetes induction. Diabetes mellitus (DM) was induced by low-dose injections of streptozotocin (50 mg/kg) for 5 consecutive days. Eight weeks after streptozotocin injections, DM was determined by measuring blood glucose and body weight. Diabetic mice were treated with two intracavernous administrations of phosphate-buffered saline (20 μL) or various doses of HB-EGF (days -3 and 0; 1, 5, and 10 μg in 20 μL of phosphate-buffered saline). The angiogenesis effect of HB-EGF was confirmed by tube formation and migration assays in mouse cavernous endothelial cells and mouse cavernous pericytes under high-glucose conditions. Erectile function was measured by electrical stimulation of the cavernous nerve, as well as histological examination and Western blot analysis for mechanism assessment.
RESULTS: In vitro angiogenesis, cell proliferation, in vivo intracavernous pressure, neurovascular regeneration, cavernous permeability, and survival signaling were the outcomes measured.
RESULTS: Expression of HB-EGF was reduced under diabetic conditions. Exogenous HB-EGF induced angiogenesis in mouse cavernous endothelial cells and mouse cavernous pericytes under high-glucose conditions. Erectile function was decreased in the DM group, whereas administration of HB-EGF resulted in a significant improvement of erectile function (91% of the age-matched control group) in association with increased neurovascular content, including cavernous endothelial cells, pericytes, and neuronal cells. Histological and Western blot analyses revealed a significant increase in the permeability of the corpus cavernosum in DM mice, which was attenuated by HB-EGF treatment. The protein expression of phospho-Akt Ser473 and phosphorylated endothelial nitric oxide synthase Ser1177 increased after HB-EGF treatment.
CONCLUSIONS: The use of HB-EGF may be an effective strategy to treat ED associated with DM or other neurovascular diseases.
UNASSIGNED: Similarly to other pro-angiogenic factors, HB-EGF has dual roles in vascular and neuronal development. Our study focused on broadly evaluating the role of HB-EGF in diabetic ED. In view of the properties of HB-EGF as an angiogenic factor, its dose concentration should be strictly controlled to avoid potential side effects.
CONCLUSIONS: In the diabetic ED mouse model in this study erectile function was improved by HB-EGF, which may provide new treatment strategies for patients with ED who do not respond to phosphodiesterase 5 Inhibitors.