Abstract
Purpose: :
Activity of the urea cycle enzyme arginase has been strongly implicated in peripheral vascular dysfunction. Arginase competes with nitric oxide synthase (NOS) for their common substrate L-arginine. This can reduce NO formation which will reduce blood flow and increase platelet aggregation and leukocyte adhesion. We have found that deletion of arginase 1 blocks the decline of NO production and prevents leukocyte adhesion during acute retinal inflammation. This study determined the role of arginase in diabetes-induced retinal vascular dysfunction.
Methods: :
Retinal vascular function was analyzed in streptozotocin-diabetic or wild type and arginase 1 deficient (A1+/-) mice by using a mouse funduscope. After eight weeks of diabetes, anesthetized mice were infused intravenously with either acetylcholine (ACh) or sodium nitroprusside (SNP) to elicit endothelial-dependant or independent vasodilation, respectively. Retinal images captured with the funduscope were used to measure vasodilation. Studies were also performed in isolated central retinal arteries from STZ diabetic rats.
Results: :
Normoglycemic wild-type and A1+/- mice responded equally well to both ACh and SNP with a maximum increase in retinal artery diameter of ~40%. Diabetic mice had a blunted maximum vasodilatory response to ACh (to ~15%), but not to SNP. Maximum vasorelaxation to ACh was largely preserved in A+/- STZ mice (at ~33%) as compared with wild type mice. ACh-induced vasorelaxation was similarly impaired in retinal arteries from STZ diabetic rats. This effect was partially prevented by treatment with an arginase inhibitor. Diabetes also increased retinal arginase activity and A1 expression as compared with the control group.
Conclusions: :
Diabetes-induced impairment of ACh dependant retinal vasorelaxation is associated with increases in arginase activity and expression of arginase 1. Deletion of one copy of arginase 1 or inhibition of arginase activity largely prevents retinal vascular dysfunction, supporting the involvement of this enzyme in the development of diabetic retinopathy.
Keywords: diabetic retinopathy • nitric oxide • inner retina dysfunction: biochemistry and cell biology