3 VEGF与PEDF在DR中的相互作用及影响

    血管的发生是由血管刺激因子和血管抑制因子的平衡所控制，正常组织中，血管抑制因子影响占据优势，因此不会发生新生血管，病理状态下如：PDR，肿瘤发生时，血管刺激因子增强或/ 和抑制因子减弱，导致新生血管产生。Zhang 等[31]的实验证明，作为主要血管刺激因子的VEGF和潜在的血管抑制因子PEDF之间的平衡对调节血管渗漏与新生血管的形成是至关重要的。现已证明，VEGF与PEDF之间存在一种互逆的调节，PEDF可以大大下调视网膜血管内皮细胞和Müller细胞VEGF的表达,在Müller细胞中，用siRNA使PEDF基因沉没，可以造成VEGF在mRNA水平及蛋白质水平明显升高，说明PEDF是一种内源性的VEGF的负性调节剂。更进一步的研究表明，缺氧不仅可诱导VEGF启动子活性增加，还可诱导缺氧诱导因子（hypoxia inducing factor, HIF）核转位及促分裂原活化蛋白激酶（MAPK）磷酸化，而以上过程可被PEDF抑制。这说明PEDF抑制VEGF发生在转录水平。又有体外实验表明，PEDF可与VEGF竞争VEGFR-2，这显示出了PEDF的又一作用机制。另一方面，VEGF明显下调PEDF的表达。并由此推测，糖尿病患者视网膜局部VEGF表达增加至少部分归因与PEDF水平的减少，既而造成血管渗漏和新生血管形成。所以，恢复血管刺激因子与血管抑制因子的平衡状态，是治疗DR的关键所在。

    总之，DR的发生是一个很复杂的病理过程，它是多因素，多阶段作用的结果。在引起DR的多方面因素中，根本的原因是机体糖代谢紊乱与微循环障碍，视网膜局部血管刺激因素与血管抑制因素之间的网络平衡破坏是引发血—视网膜屏障破坏、新生血管生成的直接原因。在临床上，有效的视网膜激光光凝及玻璃体手术已成为PDR常规治疗手段。但这些方法对眼局部均具有不同程度的损伤性。目前，研究的热点逐渐从血管生成因子转移到血管生成因子与抑制因子的网络调控上。在DR的药物干预方面，旨在寻求调节关键生长因子的药物性治疗，抑制VEGF的表达，VEGF受体拮抗剂，VEGF的细胞内信号转导以及重塑VEGF与PEDF之间的动态平衡成为研究的靶方向，同时，PEDF具有抑制病理性新生血管和神经营养双重生物功能可以在治疗疾病的同时保护视功能，但是，DR有关VEGF和PEDF药物治疗的研究还处于早期阶段，还需要大量基础及药理研究来证明其临床有效性和安全性。

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