編者按 DR新生血管形成機制的探索 DR的病理改變主要是視網膜毛細血管內皮損害，包括選擇性周細胞喪失、基底膜增厚、毛細血管閉塞和因血視網膜屏障功能受損發生的滲漏，導致廣泛的視網膜缺血，晚期導致視網膜水腫和新生血管形成。DR的發病機制極為復雜，在高血糖的基礎上，多種機制參與其發病過程[6,7]，如多元醇通道活性的增加、蛋白激酶C（PKC）的激活、己糖胺通路的激活、視網膜的氧化損傷、非酶糖基化終末產物（AGEs）形成增加等。但具體的分子機制還未完全明了，仍是當眼科學者們關注的熱點。
糖尿病最重要的表現是高血糖狀態。血糖升高，導致UDP-GlcNAc供體增加，蛋白質的O-GlcNAc糖基化修飾增強。在以往的研究中發現，O-GlcNAc糖基化修飾在糖尿病性心肌病和糖尿病性腎病的發病過程中起到重要作用[10,11]，而近期研究指出，O-GlcNAc糖基化修飾在DR進程中也具有類似的作用[12]。在高糖培養的視網膜內皮細胞中，參與糖基化過程的糖基轉移酶及其糖基化產物發生改變[13]。在糖尿病鼠視網膜組織中，蛋白質的O-糖基化修飾水平上調[14]。
新生血管形成是DR進入增殖期的標志。視網膜新生血管破裂，引起玻璃體出血，刺激視網膜血管收縮，引起牽拉性視網膜脫離，是造成DR患者視力損害的主要原因[15,16]。新生血管形成是一個動態平衡的過程，受到促血管生成因子如血管內皮生長因子（vascular endothelial growth factor，VEGF）以及抗血管生成因子如色素上皮衍生因子（pigment epithelium derived factor，PEDF）的共同調控[17]。在促血管生成因子作用下，血管內皮細胞增殖、遷移、形成管腔，進而形成新生血管。目前，眼內注射抗VEGF藥物治療DR新生血管取得了較好的治療效果，但眼內注射抗-VEGF藥物有一定的副作用，例如眼內出血、眼內炎、神經網膜損傷、缺血-再灌注損傷等[18-21]。因此，眼科學者們仍然對促進DR新生血管形成的新靶點和新機制進行不懈探索。
以往研究發現，在高糖培養的視網膜細胞中，轉錄因子特異性蛋白1（transcription factor specificity protein 1，Sp1）的O-GlcNAc糖基化修飾能促進VEGF的表達[22]，VEGF表達上調是DR新生血管產生的直接原因，上述發現表明O-GlcNAc糖基化修飾可能與視網膜新生血管形成存在某種關聯。
Runt相關轉錄因子1（Runt-related Transcription Factor 1，RUNX1）是RUNX轉錄因子家族的一員，在細胞譜系分化方向的決定、正常造血細胞的形成和干細胞增殖中均發揮重要作用[23]。以往的研究發現，在低氧誘導的視網膜新生血管模型小鼠中，抑制RUNX1能明顯抑制模型小鼠視網膜新生血管的形成；在HRMECs中敲除RUNX1，細胞的成管能力下降[24]，說明RUNX1有明確的促血管生成作用，但其機制還不明了。
新進展：O-GlcNAc糖基化修飾與RUNX1和DR新生血管之間的關聯
小結：未來，可通過對修飾位點的測序和突變進行更深入的機制探究，期待有更多新的發現，還DR患者光明視界。
參考文獻
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（來源：《國際眼科時訊》編輯部）
