Vascular endothelial growth factor gene regulation and action in diabetic retinopathy.
Vascular endothelial growth factor gene regulation and action in diabetic retinopathy.
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DOI：
10.1016/s0896-1549(01)00010-4
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发表时间：
2002-03-01
期刊：
影响因子：
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通讯作者：
Adamis, Anthony P
中科院分区：
文献类型：
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作者：
Lu, Ming;Adamis, Anthony P
可以想象，在糖尿病视网膜病变的早期阶段，抑制血管内皮生长因子可以防止水肿的形成。然而，一旦视网膜不可逆转地缺血或形成新的血管，拮抗血管内皮生长因子可能会由于慢性缺血而导致视网膜坏死。另一种方法是诱导新生血管成熟。一旦新血管成熟，视网膜缺血就会消失。不会有水肿、出血或视网膜脱离。急性应用一种名为血管生成素-1的血管生成分子可保护血管系统免于泄漏[103]。血管生成素与内皮细胞特异性受体Tie 2结合，在血管发育，尤其是血管成熟过程中发挥重要作用。建议的机制包括招募周细胞和组织血管基质[103]。由于血管内皮生长因子在正常眼睛中呈低水平表达[46]，它可能有助于维持血管的完整性。因此，过度抑制血管内皮生长因子的表达可能对视网膜血管系统有害。抑制血管内皮生长因子的作用可能需要以一种严格调控的方式进行，这样既可以避免完全抑制，又可以维持基础水平，并在需要急性血管生成反应时提供快速逆转抑制[72]。血管内皮生长因子参与成人的正常血管生成过程，如心脏侧支循环、伤口愈合和月经周期[27]。为了避免副作用，局部给药似乎比全身给药更有吸引力。一些血管内皮生长因子拮抗剂，如血管内皮生长因子受体嵌合蛋白和血管内皮生长因子中和抗体等，都是大分子，在组织中扩散较差。由于潜在的视网膜脱离和细菌感染的并发症，重复的侵入性手术，如玻璃体内注射，似乎是不切实际的。经巩膜向脉络膜和视网膜输送生物活性蛋白质和DNA的最新进展为局部输送治疗剂提供了良好的前景[12，13]。
It is conceivable that VEGF inhibition may prevent edema formation at the early stages of diabetic retinopathy. Once the retina is irreversibly ischemic or new vessels have formed, however, antagonizing VEGF may lead to retinal necrosis due to chronic ischemia. An alternative approach would be the induction of neovascular maturation. Once the new vessels become mature, retina ischemia resolves. There would be no edema, hemorrhage, or retinal detachment. Acute administration of an angiogenic molecule called angiopoietin-1 protects vasculature from leaking [103]. Angiopoietins bind to the endothelial cell-specific receptor Tie 2 and play an important role is vascular development, especially vessel maturation. The proposed mechanisms include recruiting pericytes and organizing vascular matrix [103]. Since VEGF is constitutively expressed at low levels in normal eyes [46], it may contribute to the maintenance of vascular integrity. Thus, oversuppression of VEGF expression may be harmful to the retinal vasculature. Inhibiting VEGF action may need to be delivered in a tightly regulated manner such that complete inhibition may be avoided both to maintain basal levels and to provide rapid reversal of inhibition when acute angiogenic responses are desired [72]. VEGF is involved in normal angiogenic processes in adults such as cardiac collateral circulation, wound healing and menstrual cycle [27]. Local drug delivery seems to be more appealing than systemic administration to avoid the side effects. Some VEGF antagonists, such as VEGF receptor chimeric protein and the VEGF neutralizing antibodies are large molecules with poor diffusion into tissues. Repetitive invasive procedures such as intravitreal injection seem to be impractical due to potential complications of retinal detachment and bacterial infection. Recent progress on transscleral delivery of bioactive proteins and DNAs to the choroid and retina provides promising future on local delivery of therapeutic agents [12,13].