Introduction. Diabetic retinopathy is a progressive blinding complication of diabetes mellitus where a decrease in the angiopoietin-1 to angiopoietin-2 ratio, as well as abnormal blood flow is well documented in patients.

Aims. To establish the efficacy of a gene therapeutic approach to improve retinal angiopoietin-1 signalling in streptozotocin-diabetic mice and study the effect on capillary blood flow speed.

Methods. Using a novel, fluorescent microbead-based imaging method, we mapped capillary blood flow speed in the retina of ketamine/xylazine-anaesthetized non-diabetic and diabetic mice, injected intravitreally with vehicle control (PBS), control vector (AAV.CMV-GFP) or a vector carrying a gene for an engineered, stabilized version of angiopoietin-1 (AAV.CMV-COMPAng1). Speed measurements were accompanied by fundus imaging, fluorescence angiography and ex vivo immunohistochemistry to assess retinal status and spatial gene expression profiles.

Results. Mean capillary flow speed was 1.41±0.09 mm/s (N=6). Flow maps showed changes in capillary blood flow decreasing with retinal eccentricity (1.2±0.2 s-1). While the effect of eccentricity (1.1±0.2 s-1) or mean capillary speed (1.24±0.12 mm/s, N=5) did not change significantly, we noted local decreases (0.93±0.09 mm/s, N=5, P<0.05) in capillary blood flow speed on the nasal side of the retina at 10 weeks after diabetes induction. Intravitreal injection of the control vector caused an exacerbation of the effects of diabetes, while AAV.CMV-COMPAng1 returned blood flow speed to control levels.

Conclusions. Our findings suggest that focal functional changes of the capillary bed occur in the streptozotocin mouse model and that the Ang1/Ang2-signaling pathway may be a viable alternative or adjunctive therapeutic target to support normal capillary blood flow in the diabetic retina.