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Impressum
Retinal VEGF induces ICAM-1 and eNOS expression and initiates early diabetic retinal leukostasis
1Joussen A. M., 2Poulaki V., 1Kirchhof B., 2Adamis A. P.
2Massachusetts Eye and Ear Infirmary, Harvard Medical School; Boston MA, USA; 1Dept. of Vitreoretinal Surgery, University of Cologne, Germany
Introduction: Leukocyte adhesion to the diabetic retinal vasculature
results in early blood-retinal barrier breakdown, capillary non-perfusion
and endothelial cell death. Previous work has shown that intercellular
adhesion molecule-1 (ICAM-1) and CD18 are required these processes. However
the relevant in vivo stimuli for ICAM-1 and CD18 expression in
diabetes remain unknown. The current study investigated the causal role
of endogenous VEGF in initiating these events.
Methods: Diabetes was induced in Long Evans rats with streptozotocin,
resulting in a 2- to 3-fold increase in retinal leukocyte adhesion. Confirmed
diabetic animals were treated systemically with a highly specific VEGF
neutralizing Flt-Fc construct (VEGF TrapA40).
Results: The results show that retinal ICAM-1 levels in VEGF TrapA40-
treated diabetic animals were reduced by 43.5% when compared to diabetic
controls (n=5, P<0.001). VEGF TrapA40 also potently suppressed diabetic
leukocyte adhesion in retinal arterioles (47%, n=11, P< 0.0001), venules
(36%, n=11, P< 0.0005), and capillaries (36%, n=11, P< 0.001). The
expression of eNOS, a likely downstream mediator of VEGF activity, was
increased in diabetic retina, but was potently suppressed with VEGF TrapA40
treatment (n=8, P<0.005). Although neutrophil CD11a, CD11b, and CD18
levels were increased in one-week diabetic animals, systemically administered
VEGF TrapA40 did not alter the expression of these adhesion molecules.
Discussion: Taken together, these data indentify endogenous VEGF
as an important early inducer of diabetic retinal ICAM-1 expression, leukocyte
adhesion and eNOS expression. The inhibition of VEGF bioactivity may prove
useful in the treatment of the earliest stages of diabetic retinopathy.
DFG Jo 324/2-1, JDFI Jo 3-2000-192 and Ernst-und Berta-Grimmke Stiftung,
Düsseldorf