Plasmalemma Vesicle-Associated Protein Has a Key Role in Blood-Retinal Barrier Loss: Am J Pathol

J. Wisniewska-Kruk, A. E. van der Wijk, H. A. van Veen, T. G. Gorgels, I. M. Vogels, D. Versteeg, C. J. Van Noorden, R. O. Schlingemann, I. Klaassen

Research output: Contribution to journal/periodicalArticleScientificpeer-review


Loss of blood-retinal barrier (BRB) properties induced by vascular endothelial growth factor (VEGF) and other factors is an important cause of diabetic macular edema. Previously, we found that the presence of plasmalemma vesicle-associated protein (PLVAP) in retinal capillaries associates with loss of BRB properties and correlates with increased vascular permeability in diabetic macular edema. In this study, we investigated whether absence of PLVAP protects the BRB from VEGF-induced permeability. We used lentiviral-delivered shRNA or siRNA to inhibit PLVAP expression. The barrier properties of in vitro BRB models were assessed by measuring transendothelial electrical resistance, permeability of differently sized tracers, and the presence of endothelial junction complexes. The effect of VEGF on caveolae formation was studied in human retinal explants. BRB loss in vivo was studied in the mouse oxygen-induced retinopathy model. The inhibition of PLVAP expression resulted in decreased VEGF-induced BRB permeability of fluorescent tracers, both in vivo and in vitro. PLVAP inhibition attenuated transendothelial electrical resistance reduction induced by VEGF in BRB models in vitro and significantly increased transendothelial electrical resistance of the nonbarrier human umbilical vein endothelial cells. Furthermore, PLVAP knockdown prevented VEGF-induced caveolae formation in retinal explants but did not rescue VEGF-induced alterations in endothelial junction complexes. In conclusion, PLVAP is an essential cofactor in VEGF-induced BRB permeability and may become an interesting novel target for diabetic macular edema therapy.
Original languageEnglish
Pages (from-to)1044-1054
Number of pages11
JournalThe American journal of pathology
Issue number4
Publication statusPublished - Apr 2016


  • Animals Blood-Retinal Barrier/*metabolism Capillary Permeability/drug effects/*physiology Diabetic Retinopathy/*metabolism Disease Models, Animal Humans Macular Edema/metabolism/pathology Mice Rats Retina/*metabolism Retinal Vessels/*metabolism/*ultrastructure Vascular Endothelial Growth Factor A/metabolism


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