Lu Ming, Adamis Anthony P
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
Ophthalmol Clin North Am. 2002 Mar;15(1):69-79. doi: 10.1016/s0896-1549(01)00010-4.
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].
可以想象，血管内皮生长因子（VEGF）抑制可能会在糖尿病性视网膜病变的早期阶段预防水肿形成。然而，一旦视网膜发生不可逆的缺血或新血管已经形成，拮抗VEGF可能会由于慢性缺血导致视网膜坏死。另一种方法是诱导新生血管成熟。一旦新血管成熟，视网膜缺血就会消退。就不会有水肿、出血或视网膜脱离。急性给予一种名为血管生成素-1的血管生成分子可保护血管不渗漏[103]。血管生成素与内皮细胞特异性受体Tie 2结合，并在血管发育尤其是血管成熟中发挥重要作用。提出的机制包括募集周细胞和组织血管基质[103]。由于VEGF在正常眼睛中以低水平持续表达[46]，它可能有助于维持血管完整性。因此，过度抑制VEGF表达可能对视网膜血管有害。抑制VEGF的作用可能需要以严格调控的方式进行，以便在需要急性血管生成反应时避免完全抑制，既能维持基础水平，又能迅速逆转抑制[72]。VEGF参与成年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]。局部药物递送似乎比全身给药更具吸引力，以避免副作用。一些VEGF拮抗剂，如VEGF受体嵌合蛋白和VEGF中和抗体是大分子，向组织中的扩散性较差。由于存在视网膜脱离和细菌感染等潜在并发症，诸如玻璃体内注射等重复性侵入性操作似乎不切实际。生物活性蛋白和DNA经巩膜递送至脉络膜和视网膜的最新进展为治疗剂的局部递送提供了光明的前景[12,13]。
