Abstract
Purpose :
There is still no idealized model which mimics the complex pathogenesis of diabetic retinopathy (DR) completely. Pericyte loss in retinal vascular is common early phenomenon of DR, and is thought to be implicated in the progression of DR. It is known that platelet-derived growth factor receptor beta (PDGFRβ) has an important role on pericyte coverage and maturation of vessels. The purpose of this study was to establish a model of retinal pericyte loss by administration of STI-571, PDGFR inhibitor, using neonatal mice.
Methods :
STI-571 (100 mg/kg/day) was injected intraperitoneally twice a daily to neonatal ICR mice from postnatal day 1 (P1) to day 7. Distilled water was used as a vehicle control. The animals were euthanized at P8, and the eyes were removed for following analysis. Pericyte loss and vascular leakage in retina were evaluated by whole-mount histochemical staining for PDGFRβ and fibrinogen. The percentage of fibrinogen deposition area to the total extravascular area was calculated and deposition scores are defined as follows: Grade 0, no or little deposition (less than 10%); Grade 1, mild deposition (10-30%); Grade 2, moderate deposition (30-50%); Grade 3, severe deposition (more than 50%). Vascular network was examined by Isolectin B4 staining. For evaluating retinal thickness, paraffin-embedded retinal sections were stained by hematoxylin and eosin.
Results :
Pericyte recruitment was strongly inhibited by STI-571 and pericyte coverage was reduced by 96.4% (N = 11-12, P < 0.001). In addition, the retinal vascular network of STI-571 group was apparently sparse and exhibited abnormal patterning. In STI-571 group, the radial extension of the vascular plexus from the optic nerve to periphery was reduced by 40.2% compared to control group (N = 13-16, P < 0.001) and extravascular fibrinogen deposition was remarkably increased (N = 4-5, P = 0.0219). Furthermore, increases in retinal thickness were shown in a number of mice in STI-571 group (4/6).
Conclusions :
The administration of PDGFR inhibitor STI-571 caused the pericyte loss, the increase of retinal vascular permeability and the decrease of vessel number and radius. These results suggested that the retinas of mice treated with STI-571 were characterized by the clinical phenotypes of DR. Therefore, this model may be useful for the DR research and evaluation of drugs for DR treatment.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.