Endothelial cell hypertrophy induced by vascular endothelial growth factorin the retina - New insights into the pathogenesis of capillary nonperfusion

Objective: To investigate the mechanism leading to capillary nonperfusion o f the retina in a monkey model of vascular endothelial growth factor A (VEG F)-induced retinopathy in which capillary closure occurs in a late stage af ter VEGF treatment. Methods: Two monkeys received 4 intravitreous injections of 0.5 mug of VEGF in one eye and of phosphate-buffered saline in the other eye and were kill ed at day 9. After perfusion and enucleation, retinal samples were snap fro zen for immunohistochemical analysis with the panendothelial cell marker CD 31 or were fixed for morphometric analysis at the light and electron micros copic level. Results: At the light microscopic level, all capillaries in the retina of V EGF-injected eyes displayed hypertrophic walls with narrow lumina. In a qua ntitative analysis of the deep capillary plexus in the inner nuclear layer, VEGF-injected eyes had a significant 5- to 7-fold decrease in total capill ary luminalvolume. CD31 staining showed that this decrease was not accompan ied by a change in the number of capillaries. Electron microscopy revealed that the luminal volume of individual capillaries of the inner nuclear laye r of VEGF-injected eyes was significantly decreased due to a 2-fold hypertr ophy of the endothelial cells. Conclusions: Luminal narrowing caused by endothelial cell hypertrophy occur s in the deep retinal capillary plexus in VEGF-induced retinopathy in monke ys. This suggests a causal role of endothelial cell hypertrophy in the path ogenesis of VEGF-induced retinal capillary closure. A similar mechanism may operate in retinal conditions in humans associated with ischemia and VEGF overexpression. Clinical Relevance: Capillary nonperfusion occurs in diabet ic retinopathy and other ischemic diseases associated with overexpression o f VEGF. In addition, VEGF-induced endothelial cell hypertrophy may be causa tive for capillary closure in these diseases.