VEGF-initiated blood-retinal barrier breakdown in early diabetes.
OBJECTIVE
The objectives of this study were to (1) determine whether endogenous vascular endothelial growth factor (VEGF) triggers diabetic blood-retinal barrier breakdown, and (2) identify the site as well as phenotype of the hyperpermeable diabetic retinal vessels.


METHODS
Retinal VEGF mRNA levels were quantified in 1-week diabetic rats using the RNase protection assay. VEGF bioactivity was blocked via the systemic administration of a highly specific VEGF-neutralizing soluble Flt/F(c) construct (VEGF TrapA(40)). An inactive IL6 receptor/F(c) construct (IL6R Trap) was used as an isotype control. Blood-retinal barrier breakdown was quantified using the Evans blue technique and was spatially localized with fluorescent microspheres.


RESULTS
Retinal VEGF mRNA levels in 1-week diabetic animals were 3.2-fold higher than in nondiabetic controls (P < 0.0001). Similarly, retinal vascular permeability in 8-day diabetic animals was 1.8-fold higher than in normal nondiabetic controls (P < 0.05). Diabetes-induced blood-retinal barrier breakdown was dose-dependently inhibited with VEGF TrapA(40), with 25 mg/kg producing complete inhibition of the diabetes-induced increases (P < 0.05). Blood-retinal barrier breakdown in diabetic animals treated with solvent alone or IL6R Trap did not differ significantly from untreated diabetic animals (P > 0.05). Spatially, early blood-retinal barrier breakdown was localized to the retinal venules and capillaries of the superficial retinal vasculature.


CONCLUSIONS
Early blood-retinal barrier breakdown in experimental diabetes is VEGF dependent and is restricted, in part, to the venules and capillaries of the superficial inner retinal vasculature. VEGF inhibition should prove a useful therapeutic approach in the treatment of early diabetic blood-retinal barrier breakdown.
Qaum
T
T
Department of Surgical Research, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Xu
Q
Q
Joussen
A M
AM
Clemens
M W
MW
Qin
W
W
Miyamoto
K
K
Hassessian
H
H
Wiegand
S J
SJ
Rudge
J
J
Yancopoulos
G D
GD
Adamis
A P
AP
D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D004396:Coloring Agents; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D005070:Evans Blue; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004396:Coloring Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D005070:Evans Blue