Vascular endothelial growth factor gene regulation and action in diabetic retinopathy

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].