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¶
From the Massachusetts Eye and Ear Infirmary,*
Boston,Massachusetts; the Surgical ResearchLaboratory,
Children’s Hospital, Boston,Massachusetts; the Dana-Farber CancerInstitute,
Boston, Massachusetts; RegeneronPharmaceuticals,
Tarrytown, New York; and theDepartment of Vitreoretinal Surgery,¶
Center forOphthalmology and Zentrum für Molekulare Medizin, University ofCologne, Köln, Germany
Leukocyte adhesion to the diabetic retinal vasculature results in
early blood-retinal barrier breakdown, capillary
nonperfusion, and endothelial cell injury and death. Previous
work has shown that intercellular adhesion molecule-1 (ICAM-1) and CD18
are required for 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
vascular endothelial growth factor (VEGF) and nitric oxide in
initiating these events. Diabetes was induced in Long-Evans rats with
streptozotocin, resulting in a two- to threefold increase in
retinal leukocyte adhesion. Confirmed diabetic animals were treated
with a highly specific VEGF-neutralizing Flt-Fc construct (VEGF
TrapA40). Retinal ICAM-1 mRNA levels in VEGF
TrapA40-treated diabetic animals were reduced by 83.5%
compared to diabetic controls (n = 5,
P < 0.0001). 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
endothelial nitric oxide synthase (eNOS), a downstream mediator
of VEGF activity, was increased in diabetic retina, and
was potently suppressed with VEGF TrapA40 treatment
(n = 8, P < 0.005).
Further, VEGF TrapA40 reduced the diabetes-related
nitric oxide increases in the retinae of diabetic animals. The
inhibition of eNOS with N-
-nitro-L-arginine methyl ester
also potently reduced retinal leukocyte adhesion. Although neutrophil
CD11a, CD11b, and CD18 levels were increased in 1-week
diabetic animals, VEGF TrapA40 did not alter the
expression of these integrin adhesion molecules. Taken
together, these data demonstrate that VEGF induces retinal
ICAM-1 and eNOS expression and initiates early diabetic retinal
leukocyte adhesion in vivo. The inhibition of VEGF
bioactivity may prove useful in the treatment of the early diabetic
retinopathy.
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