Attenuation of streptozotocin-induced microvascular changes in the mouse retina with the endothelin receptor A antagonist atrasentan

Abstract

Hyperglycemia mediates endothelial cell dysfunction through a number of potential mechanisms that could result in the decrease of retinal blood flow early in diabetes. The aim of this study was to explore the role of endothelin receptor A (ETA) in the early decrease of retinal blood flow in diabetic mice. Diabetes was induced by streptozotocin, then ~1 wk later the mice were administered drinking water with or without the ETA receptor antagonist atrasentan (7.5 mg/kg/day) for the following 3 weeks. Non-diabetic age-matched mice with or without atrasentan were included as controls. For each mouse, measurements of retinal vascular diameters and red blood cell (RBC) velocities were obtained via intravital microscopy for the 5–7 feed arterioles (and draining venules) extending out of (and into) the optic disk, and from these values, flow rates and wall shear rates were calculated. Additionally, the number of retinal capillaries was counted by fluorescent immunostaining of platelet-endothelial cell adhesion molecule-1 (PECAM-1). Diabetes induced statistically significant decreases in RBC velocity, flow rate, and wall shear rate, with these alterations partially inhibited by atrasentan. No changes were observed in PECAM-1 expression among groups. The changes induced by diabetes, and the attenuation provided by atrasentan, were greater in the smaller retinal arterioles. In summary, ETA appears to play a role in the early decreases in retinal blood flow in a mouse model of diabetes.

Inner Retinal Oxygen Delivery, Metabolism, and Extraction Fraction in Ins2Akita Diabetic Mice

“…They are also similar to other reported reductions in F values in STZ-diabetic mice. 32–36 Had these investigators measured O 2A , it is likely that they would have found decreases in DO 2 similar to the decrease of 43% in the current study. These defective DO 2 and F responses in diabetes likely correspond to the well-known impaired autoregulation seen in humans with diabetes.…”

Effect of Tempol on Diabetes-Induced Decreases in Retinal Blood Flow in the Mouse

“…Other vasoconstricting pathways also are likely to be involved, and we have obtained evidence for contributing roles of thromboxane, angiotensin II, and endothelin-1. [3][4][5] However, the extent of overlap between these vasoconstrictors with the mechanisms induced by reactive oxygen species has yet to be determined, although there is evidence of a significant link between angiotensin II and oxidative stress. 19 Tempol may enhance the effects of the vasodilator nitric oxide (NO) by several mechanisms, as reviewed by Wilcox and Pearlman 7 : (1) by preventing the bioinactivation of NO by superoxide, (2) by enhancing shear-induced endothelial production of NO, (3) by interrupting the incorporation of NO into glutathione to form S-nitrosoglutathione, (4) by increasing the activity of the redox-sensitive dimethylarginine dimethylaminohydrolase, which inactivates the NO synthase inhibitor asymmetric dimethylarginine, and (5) by improving the availability of the reduced form of tetrahydrobiopterin and thereby recoupling NO synthase.…”

“…7 Studies from other labs have demonstrated significant diabetes-induced increases in superoxide production in mice and rats early in the progression of disease. [8][9][10][11][12] In studies from our lab, we see a decrease in retinal blood flow occurring as early as 3-4 weeks following induction of diabetes, [3][4][5]13 and herein test the hypothesis that tempol administration may attenuate this decrease.…”

Imaging of Hypoxia in Retinal Vascular Disease

“…Some studies in diabetic mice show that there is an initial decrease in retinal blood flow between three to 4 weeks due to arteriolar constriction, however arteriolar diameter and blood flow return to normal measurements at later time points of diabetes (12 weeks) [49][50][51][52]. Despite the initial decrease in blood flow these studies did not find any evidence of hypoxia in these animals at either 3 or 12 weeks of diabetes [53][54][55].…”