Purchase this article with an account.
K.M. Harrison, J.L. Edelman; Complete Suppression of VEGF121 or VEGF165–Mediated Retinal Inflammation, Increases in Retinal Vessel Caliber/Tortuosity, and BRB Breakdown by an Intravitreal Dexamethasone Drug Delivery System . Invest. Ophthalmol. Vis. Sci. 2006;47(13):504.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
These studies were designed to evaluate the effects of intravitreal VEGF121 on changes in retinal vessel caliber and tortuosity (blood flow), blood–retinal barrier (BRB) breakdown, and inflammatory cell homing and migration in rabbits. Furthermore, we evaluated the effects of pretreatment with an intravitreal dexamethasone (DEX) drug delivery system (DDS) on VEGF121 and VEGF165–mediated responses.
500 ng of either VEGF121 or VEGF165 were injected intravitreally into the eyes of Dutch Belt rabbits. Forty–eight hours later, fundus images and fluorescein angiograms were obtained for subjective grading of changes in retinal vessel caliber/vessel tortuosity and fluorescein leakage. Vitreoretinal fluorescein leakage was also measured by fluorophotometry. At 48 hours after intravitreal injection, VEGF121 treated and untreated control eyes were fixed in 4% paraformaldehyde and preserved in 10% formalin. Paraffin sections through the myelinated vascular region of each retina were stained with either H&E or immunostaining for either RAM11 (monocyte/macrophage) or CD3 (T–cell). In pharmacology studies, rabbits received either 700 µg of a DEX–DDS or a sham injection two weeks prior to growth factor injection.
As reported previously, 500 ng VEGF165 causes BRB breakdown and increases retinal vasodilation/ tortuosity compared to untreated eyes (p<0.0001). Similar to the effects of the larger VEGF splice variant, 500 ng intravitreal VEGF121 induces severe BRB breakdown and increases retinal vasodilation/tortuosity compared to control eyes (p<0.0001). The effects of VEGF121 are not significantly different from those of VEGF165. Histologic examination of VEGF121–treated eyes shows an increase in leukocyte adhesion to retinal blood vessels and significantly more RAM–11 positive macrophages within the retina compared to control eyes. Pretreatment with a DEX–DDS completely blocks breakdown of the blood–retinal–barrier and increases in vessel caliber/tortuosity mediated by either VEGF121 or VEGF165 (p<0.0004).
VEGF121 and VEGF165 elicit proinflammatory responses in the retina that are completely blocked by pretreatment with dexamethasone delivered intravitreally via a novel drug delivery system. These results suggest that intravitreal dexamethasone therapy may be useful in treating retinal diseases characterized by signaling via multiple VEGF splice variants.
This PDF is available to Subscribers Only