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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Nippert, Amy R; Biesecker, Kyle R; Newman, Eric A (2018) Mechanisms Mediating Functional Hyperemia in the Brain. Neuroscientist 24:73-83
Srienc, Anja I; Biesecker, Kyle R; Shimoda, Angela M et al. (2016) Ischemia-induced spreading depolarization in the retina. J Cereb Blood Flow Metab 36:1579-91
Biesecker, Kyle R; Srienc, Anja I; Shimoda, Angela M et al. (2016) Glial Cell Calcium Signaling Mediates Capillary Regulation of Blood Flow in the Retina. J Neurosci 36:9435-45
MacVicar, Brian A; Newman, Eric A (2015) Astrocyte regulation of blood flow in the brain. Cold Spring Harb Perspect Biol 7:
Kornfield, Tess E; Newman, Eric A (2015) Measurement of Retinal Blood Flow Using Fluorescently Labeled Red Blood Cells. eNeuro 2:
Newman, Eric A (2015) Glial cell regulation of neuronal activity and blood flow in the retina by release of gliotransmitters. Philos Trans R Soc Lond B Biol Sci 370:
Kur, Joanna; Newman, Eric A (2014) Purinergic control of vascular tone in the retina. J Physiol 592:491-504
Kornfield, Tess E; Newman, Eric A (2014) Regulation of blood flow in the retinal trilaminar vascular network. J Neurosci 34:11504-13
Newman, Eric A (2013) Functional hyperemia and mechanisms of neurovascular coupling in the retinal vasculature. J Cereb Blood Flow Metab 33:1685-95
Kur, Joanna; Newman, Eric A; Chan-Ling, Tailoi (2012) Cellular and physiological mechanisms underlying blood flow regulation in the retina and choroid in health and disease. Prog Retin Eye Res 31:377-406

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