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New Insights Into the Pathogenesis of Capillary Nonperfusion

Pim Hofman, BSc; Bart C. van Blijswijk, MSc; Pieter J. Gaillard, PhD; Gijs F. J. M. Vrensen, PhD; Reinier O. Schlingemann, MD, PhD

Arch Ophthalmol. 2001;119:861-866.

Objective  To investigate the mechanism leading to capillary nonperfusion of the retina in a monkey model of vascular endothelial growth factor A (VEGF)–induced retinopathy in which capillary closure occurs in a late stage after VEGF treatment.

Methods  Two monkeys received 4 intravitreous injections of 0.5 µg of VEGF in one eye and of phosphate-buffered saline in the other eye and were killed at day 9. After perfusion and enucleation, retinal samples were snap frozen for immunohistochemical analysis with the panendothelial cell marker CD31 or were fixed for morphometric analysis at the light and electron microscopic level.

Results  At the light microscopic level, all capillaries in the retina of VEGF-injected eyes displayed hypertrophic walls with narrow lumina. In a quantitative analysis of the deep capillary plexus in the inner nuclear layer, VEGF-injected eyes had a significant 5- to 7-fold decrease in total capillary luminal volume. CD31 staining showed that this decrease was not accompanied by a change in the number of capillaries. Electron microscopy revealed that the luminal volume of individual capillaries of the inner nuclear layer of VEGF-injected eyes was significantly decreased due to a 2-fold hypertrophy of the endothelial cells.

Conclusions  Luminal narrowing caused by endothelial cell hypertrophy occurs in the deep retinal capillary plexus in VEGF-induced retinopathy in monkeys. This suggests a causal role of endothelial cell hypertrophy in the pathogenesis 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 diabetic retinopathy and other ischemic diseases associated with overexpression of VEGF. In addition, VEGF-induced endothelial cell hypertrophy may be causative for capillary closure in these diseases.

From the Ocular Angiogenesis Group, Department of Ophthalmology, Academic Medical Center (Messrs Hofman and van Blijswijk and Drs Gaillard and Schlingemann), and Department of Morphology, Netherlands Ophthalmic Research Institute (Messrs Hofman and van Blijswijk and Drs Gaillard and Vrensen), Amsterdam, the Netherlands.

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