Stimulating the eye with light results in an increase in retinal blood flow, a response termed functional hyperemia. This response, which supplies active neurons with oxygen and nutrients, is essential for healthy retinal function. Functional hyperemia is disrupted in several retinal pathologies, including diabetic retinopathy, where the response is dramatically reduced. The mechanisms mediating functional hyperemia are not well understood. The goals of the proposed project are to determine i) how blood flow is regulated in the retina, ii) why functional hyperemia is disrupted in the diabetic retina, and iii) whether functional hyperemia can be restored by inhibiting inducible nitric oxide synthase (iNOS). Experiments will be conducted on the rat intact-globe in vivo preparation.
The specific aims for the project period are:
Aim 1. Determine whether capillaries contribute to the regulation of blood flow in the retina. Blood flow through capillaries will be monitored to test whether a greater fraction of capillaries are functionally perfused during photopic stimulation. Capillary control of blood flow is of particular interest as pericytes, the contractile cells that control blood flow through capillaries, are one of the first retinal cells to die in diabetic retinopathy.
Aim 2. Test the hypothesis that glial cells mediate functional hyperemia in the retina. Glial cells will be selectively stimulated by photolysis of caged Ca2+ while monitoring blood flow to determine whether these cells evoke vasomotor responses. Light-evoked changes in blood flow will be monitored to determine whether functional hyperemia is blocked when neuron-to-glia signaling is interrupted by addition of a purinergic signaling antagonist. Determining whether glial cells mediate functional hyperemia will help in the development of therapies for preventing or reversing the loss of function hyperemia in the diabetic retina.
Aim 3. Determine whether inhibiting iNOS reverses the loss of functional hyperemia in the diabetic retina. Using a streptozotocin rat model of type 1 diabetes, light- and glial-evoked changes in blood flow will be characterized in control and diabetic animals. iNOS will be inhibited with aminoguanidine to test whether functional hyperemia can be restored in diabetic animals.

Public Health Relevance

Regulation of retinal blood flow is disrupted in diabetic retinopathy, which is one of the leading causes of blindness. This project will investigate the mechanisms responsible for blood flow regulation in the retina and test a therapy for restoring normal blood flow in the diabetic retina.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-P (02))
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Shen, Grace L
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University of Minnesota Twin Cities
Schools of Medicine
United States
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Kornfield, Tess E; Newman, Eric A (2014) Regulation of blood flow in the retinal trilaminar vascular network. J Neurosci 34:11504-13
Kur, Joanna; Newman, Eric A (2014) Purinergic control of vascular tone in the retina. J Physiol 592:491-504
Newman, Eric A (2013) Functional hyperemia and mechanisms of neurovascular coupling in the retinal vasculature. J Cereb Blood Flow Metab 33:1685-95
Srienc, Anja I; Kornfield, Tess E; Mishra, Anusha et al. (2012) Assessment of glial function in the in vivo retina. Methods Mol Biol 814:499-514
Mishra, Anusha; Hamid, Arif; Newman, Eric A (2011) Oxygen modulation of neurovascular coupling in the retina. Proc Natl Acad Sci U S A 108:17827-31
Mishra, Anusha; Newman, Eric A (2010) Inhibition of inducible nitric oxide synthase reverses the loss of functional hyperemia in diabetic retinopathy. Glia 58:1996-2004
Kurth-Nelson, Zeb L; Mishra, Anusha; Newman, Eric A (2009) Spontaneous glial calcium waves in the retina develop over early adulthood. J Neurosci 29:11339-46
Clark, Benjamin D; Kurth-Nelson, Zeb L; Newman, Eric A (2009) Adenosine-evoked hyperpolarization of retinal ganglion cells is mediated by G-protein-coupled inwardly rectifying K+ and small conductance Ca2+-activated K+ channel activation. J Neurosci 29:11237-45
Metea, Monica R; Kofuji, Paulo; Newman, Eric A (2007) Neurovascular coupling is not mediated by potassium siphoning from glial cells. J Neurosci 27:2468-71
Metea, Monica R; Newman, Eric A (2007) Signalling within the neurovascular unit in the mammalian retina. Exp Physiol 92:635-40

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