Thrombospondin-1 Deficiency Exacerbates the Pathogenesis of Diabetic Retinopathy.
Diabetic retinopathy is a leading cause of blindness in the United States. Access to new animal models that exhibit retinal vasculopathies with short duration of diabetes, are vital for understanding the underlying mechanisms and examining the efficacy of new treatment modalities. Our previous studies demonstrated decreased expression of Thrombospondin-1 (TSP1), an endogenous inhibitor of angiogenesis, in eyes from both patients and rodents with diabetes. Here we examined whether TSP1 deficiency could exacerbate diabetic retinal vasculopathies. Akita/+ male mice reproducibly develop diabetes by 4 weeks of age. These mice demonstrated the early non-proliferative stages of diabetic retinopathy, including decreased numbers of pericytes and increased glial cell activation. However, Akita/+ male mice deficient in TSP1 (Akita/+; TSP1-/-) demonstrated more advanced stages of diabetic retinopathy with a 4-fold increase in acellular capillaries and increased fibronectin and GFAP expression. These vascular changes were not attributable to aberrant retinal vascular development in the absence of TSP1, since down-regulation of TSP1 postnatally in the endothelium also resulted in more severe retinopathy. In addition, lack of another endogenous inhibitor of angiogenesis, pigment epithelium derived factor (PEDF), also enhanced diabetic retinopathy in Akita/+ mice. Akita/+; PEDF-/- male mice demonstrated increased numbers of acellular capillaries compared to controls but at a level lower than that observed in Akita/+; TSP1-/- mice. Thus, the exacerbation of diabetic retinopathy in Akita/+; TSP1-/- mice will allow the study of retinal vasculopathies with a shorter duration of diabetes and facilitate future testing of treatment modalities that protect the retinal vasculature and preserve sight.
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, USA ; McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, USA.
Christine M
CM
Sorenson
Shoujian
S
Wang
Robert
R
Gendron
Hélène
H
Paradis
Nader
N
Sheibani
Angiogenesis inhibitors; Diabetic retinopathy; PEDF; Thrombospondin-1