SCI TOP 10

当前位置:首页>SCI TOP 10

二甲基精氨酸二-2缺乏可促进血管再生并减轻病理性血管生成

Lange C, Mowat F, Sayed H, et al.

期刊名称:Experimental Eye Research

卷期:2016年第146卷

摘要

缺血诱导的血管生成是组织修复的关键,但视网膜异常新生血管形成可导致严重的视力损害。一氧化氮(NO)因为其对视网膜的促血管发生特性已参与新生血管性眼睛疾病的发病。一氧化氮产物受不对称性二甲基精氨酸(DDAH)(ADMAL-NMMA)的内源性抑制,主要由二甲基精氨酸二甲基氨基水解酶(DDAH 12代谢。本研究旨在确定DDAH1DDAH2ADMAL-NMMA在视网膜缺血诱导血管生成中的作用。首先,确定成年C57BL / 6J小鼠DDAH1DDAH2ADMAL-NMMA的水平。结果表明,视网膜上的DDAH1水平比大脑和脉络膜高2倍。 与脑组织相比,视网膜的DDAH2表达大约高150倍,脉络膜要高70倍,这提示DDAH2在视网膜和脉络膜上的的重要组织特异性。 生理条件下,视网膜和脉络膜的ADMAL-NMMA水平相似。接着,与野生型对照小鼠相比,体内荧光血管造影,免疫组织化学和视网膜电流图下DDAH1+/-)和DDAH2 - / - )缺陷小鼠的特征显示神经血管功能正常。最后,在氧诱导视网膜病(OIR)模型(可模拟视网膜缺血和新生血管形成)中研究了DDAH1+/-)和DDAH2 - / - )缺陷小鼠,并通过ELISA和液相色谱串联质谱法对血管内皮生长因子和ADMA水平进行了量化。在OIR模型中,与野生型对照相比,DDAH1+/-)表现出相似的表型。相反, DDAH2缺乏,可导致视网膜ADMA升高,而视网膜ADMA升高与异常血管生成减轻和血管再生改善相关,而与VEGF无关。综上所述,这项研究表明,在视网膜缺血中,DDAH2缺乏可致 ADMA升高,促进血管再生,预防异常血管生成。因此DDAH2的治疗性抑制可能为通过促进视网膜血管再生,防止病理性血管生成来保护视力提供潜在治疗策略。

Ischemia-induced angiogenesis is critical for tissue repair, but aberrant neovascularization in the retina causes severe sight impairment. Nitric oxide (NO) has been implicated in neovascular eye disease because of its pro-angiogenic properties in the retina. Nitric oxide production is inhibited endogenously by asymmetric dimethylarginines (ADMA and L-NMMA) which are metabolized by dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2. The aim of this study was to determine the roles of DDAH1, DDAH2, ADMA and L-NMMA in retinal ischemia-induced angiogenesis. First, DDAH1, DDAH2, ADMA and L-NMMA levels were determined in adult C57BL/6J mice. The results obtained revealed that DDAH1 was twofold increased in the retina compared to the brain and the choroid. DDAH2 expression was approximately 150 fold greater in retinal and 70 fold greater in choroidal tissue compared to brain tissue suggesting an important tissue-specific role for DDAH2 in the retina and choroid. ADMA and L-NMMA levels were similar in the retina and choroid under physiological conditions. Next, characterization of DDAH1(+/-) and DDAH2(-/-) deficient mice by in vivo fluorescein angiography, immunohistochemistry and electroretinography revealed normal neurovascular function compared with wildtype control mice. Finally, DDAH1(+/-) and DDAH2(-/-) deficient mice were studied in the oxygen-induced retinopathy (OIR) model, a model used to emulate retinal ischemia and neovascularization, and VEGF and ADMA levels were quantified by ELISA and liquid chromatography tandem mass spectrometry. In the OIR model, DDAH1(+/-) exhibited a similar phenotype compared to wildtype controls. DDAH2 deficiency, in contrast, resulted in elevated retinal ADMA which was associated with attenuated aberrant angiogenesis and improved vascular regeneration in a VEGF independent manner. Taken together this study suggests, that in retinal ischemia, DDAH2 deficiency elevates ADMA, promotes vascular regeneration and protects against aberrant angiogenesis. Therapeutic inhibition of DDAH2 may therefore offer a potential therapeutic strategy to protect sight by promoting retinal vascular regeneration and preventing pathological angiogenesis.


点击下载

CopyRight 2016  兴齐100版权所有 京ICP证060955号
技术支持:示剑网络   http://100.sinqi.com/