Understanding the microvascular changes of diabetes is crucial to the development of improved therapy. In the diabetic retina, areas of ischemic tissue are thought to lead to deficient oxygenation and the production of vascular endothelial growth factor, which enhances vascular permeability and plays a major role in retinopathy. Our preliminary data in an animal model of diabetes (streptozotocin injection) demonstrate early arteriolar constriction in the initial weeks of hyperglycemia. Experiments from our lab suggest a localized mechanism of microvascular dysfunction, in which mediators derived from inflammatory cells diffuse from venules to closely paired arterioles to induce vasoconstriction, either directly or through an attenuation of the vasodilator nitric oxide. In a related model (microvascular dysfunction in the mesentery of diabetic rats), we previously have demonstrated a substantial attenuation of nitric oxide in arterioles closely paired with postcapillary venules. We hypothesize that the same could be true in the diabetic retina, and that the attenuation in nitric oxide is related to the increase in reactive oxygen species such as superoxide. Moreover, we hypothesize that thromboxane derived locally from inflammatory cells contributes significantly to the arteriolar vasoconstriction. We have obtained exciting preliminary data (in the retina of both mice and rats) indicating that inhibition of thromboxane synthase reverses the arteriolar vasoconstriction induced by diabetes. Thromboxane is a highly potent vasoactive molecule, and can induce vasoconstriction directly by binding to its receptor on vascular smooth muscle cells. In addition, the vasoconstrictor has been found to contribute to oxidative stress, and inhibition of thromboxane acutely elevates nitric oxide bioavailability. Models of streptozotocin-induced diabetes demonstrate retinal hypoxia, increased cell death, an increase in VEGF production, and an increase in vascular permeability. We propose that vasoconstriction contributes to these deleterious consequences, and that improvements in these endpoints can be accomplished via inhibition of thromboxane and reactive oxygen species.
Our specific aims are to investigate the role for thromboxane and reactive oxygen species in the early retinal arteriolar constriction induced by diabetes, and to determine whether inhibition of vasoconstriction improves endpoints of diabetic retinal complications.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017599-04
Application #
7923146
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Shen, Grace L
Project Start
2007-09-30
Project End
2011-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
4
Fiscal Year
2010
Total Cost
$290,070
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Physiology
Type
Schools of Medicine
DUNS #
095439774
City
Shreveport
State
LA
Country
United States
Zip Code
71103
Eshaq, Randa S; Wright, William S; Harris, Norman R (2014) Oxygen delivery, consumption, and conversion to reactive oxygen species in experimental models of diabetic retinopathy. Redox Biol 2:661-6
Harris, Norman R; Watts, Megan N; Leskova, Wendy (2013) Intravital video microscopy measurements of retinal blood flow in mice. J Vis Exp :51110
Leskova, Wendy; Watts, Megan N; Carter, Patsy R et al. (2013) Measurement of retinal blood flow rate in diabetic rats: disparity between techniques due to redistribution of flow. Invest Ophthalmol Vis Sci 54:2992-9
Wright, William S; Yadav, Amit Singh; McElhatten, Robert M et al. (2012) Retinal blood flow abnormalities following six months of hyperglycemia in the Ins2(Akita) mouse. Exp Eye Res 98:9-15
Wang, Zhongli; Yadav, Amit Singh; Leskova, Wendy et al. (2011) Inhibition of 20-HETE attenuates diabetes-induced decreases in retinal hemodynamics. Exp Eye Res 93:108-13
Yadav, Amit Singh; Harris, Norman R (2011) Effect of tempol on diabetes-induced decreases in retinal blood flow in the mouse. Curr Eye Res 36:456-61
Wright, William S; McElhatten, Robert M; Busu, Carmina et al. (2011) Influence of glutathione on the electroretinogram in diabetic and non-diabetic rats. Curr Eye Res 36:831-7
Wright, William S; McElhatten, Robert M; Harris, Norman R (2011) Increase in retinal hypoxia-inducible factor-2?, but not hypoxia, early in the progression of diabetes in the rat. Exp Eye Res 93:437-41
Wright, William S; McElhatten, Robert M; Messina, Jodine E et al. (2010) Hypoxia and the expression of HIF-1alpha and HIF-2alpha in the retina of streptozotocin-injected mice and rats. Exp Eye Res 90:405-12
Wang, Zhongli; Yadav, Amit Singh; Leskova, Wendy et al. (2010) Attenuation of streptozotocin-induced microvascular changes in the mouse retina with the endothelin receptor A antagonist atrasentan. Exp Eye Res 91:670-5

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