title: Endothelial cell hypertrophy induced by vascular endothelial growth factor in the retina: new insights into the pathogenesis of capillary nonperfusion.
abstract: 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 microg 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Hofman
authors.forename: B C
authors.initials: BC
authors.lastname: van Blijswijk
authors.forename: P J
authors.initials: PJ
authors.lastname: Gaillard
authors.forename: G F
authors.initials: GF
authors.lastname: Vrensen
authors.forename: R O
authors.initials: RO
authors.lastname: Schlingemann
mesh_terms: D000818:Animals; D002196:Capillaries / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006984:Hypertrophy; D007124:Immunoenzyme Techniques; D007275:Injections, Intravenous; D008222:Lymphokines / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D015356:Retinal Artery Occlusion / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012170:Retinal Vein Occlusion / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors