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Regulation of blood flow in diabetic retinopathy

Published online by Cambridge University Press:  20 July 2020

Amy R. Nippert  and
Eric A. Newman
Amy R. Nippert
Affiliation:
Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
Eric A. Newman*
Affiliation:
Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
*
*Address correspondence to: Eric A. Newman; E-mail: [email protected]
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Abstract

Blood flow in the retina increases in response to light-evoked neuronal activity, ensuring that retinal neurons receive an adequate supply of oxygen and nutrients as metabolic demands vary. This response, termed “functional hyperemia,” is disrupted in diabetic retinopathy. The reduction in functional hyperemia may result in retinal hypoxia and contribute to the development of retinopathy. This review will discuss the neurovascular coupling signaling mechanisms that generate the functional hyperemia response in the retina, the changes to neurovascular coupling that occur in diabetic retinopathy, possible treatments for restoring functional hyperemia and retinal oxygen levels, and changes to functional hyperemia that occur in the diabetic brain.

Keywords

Diabetic retinopathyneurovascular couplingblood flowhypoxianeurovascular unitMüller cells
Type
Review Article
Information
Visual Neuroscience , Volume 37 , 2020 , E004
Copyright
© The Author(s), 2020. Published by Cambridge University Press

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References

Arden, G.B., Wolf, J.E. & Tsang, Y. (1998). Does dark adaptation exacerbate diabetic retinopathy? Evidence and a linking hypothesis. Vision Research 38, 1723–1729.CrossRefGoogle Scholar
Attwell, D., Buchan, A.M., Charpak, S., Lauritzen, M., MacVicar, B.A. & Newman, E.A. (2010). Glial and neuronal control of brain blood flow. Nature 468, 232–243.CrossRefGoogle ScholarPubMed
Bek, T., Hajari, J. & Jeppesen, P. (2008). Interaction between flicker-induced vasodilatation and pressure autoregulation in early retinopathy of type 2 diabetes. Graefe’s Archive for Clinical and Experimental Ophthalmology 246, 763–769.CrossRefGoogle ScholarPubMed
Biesecker, K.R., Srienc, A.I., Shimoda, A.M., Agarwal, A., Bergles, D.E., Kofuji, P. & Newman, E.A. (2016). Glial cell calcium signaling mediates capillary regulation of blood flow in the retina. Journal of Neuroscience 36, 9435–9445.CrossRefGoogle ScholarPubMed
Blum, M., Bachmann, K., Wintzer, D., Riemer, T., Vilser, W. & Strobel, J. (1999). Noninvasive measurement of the Bayliss effect in retinal autoregulation. Graefe’s Archive for Clinical and Experimental Ophthalmology 237, 296–300.CrossRefGoogle ScholarPubMed
Bolton, W.K., Cattran, D.C., Williams, M.E., Adler, S.G., Appel, G.B., Cartwright, K., Foiles, P.G., Freedman, B.I., Raskin, P., Ratner, R.E., Spinowitz, B.S., Whittier, F.C., Wuerth, J.P. & A, I. (2004). Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. American Journal of Nephrology 24, 32–40.CrossRefGoogle ScholarPubMed
Bonds, J.A., Shetti, A., Bheri, A., Chen, Z., Disouky, A., Tai, L., Mao, M., Head, B.P., Bonini, M.G., Haus, J.M., Minshall, R.D. & Lazarov, O. (2019). Depletion of caveolin-1 in type 2 diabetes model induces Alzheimer’s disease pathology precursors. Journal of Neuroscience 39, 8576–8583.CrossRefGoogle ScholarPubMed
Brownlee, M., Vlassara, H., Kooney, A., Ulrich, P. & Cerami, A. (1986). Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science 232, 1629–1632.CrossRefGoogle ScholarPubMed
Chen, B.R., Kozberg, M.G., Bouchard, M.B., Shaik, M.A. & Hillman, E.M. (2014). A critical role for the vascular endothelium in functional neurovascular coupling in the brain. Journal of the American Heart Association 3, e000787.CrossRefGoogle Scholar
Chhabria, K., Plant, K., Bandmann, O., Wilkinson, R.N., Martin, C., Kugler, E., Armitage, P.A., Santoscoy, P.L., Cunliffe, V.T., Huisken, J., McGown, A., Ramesh, T., Chico, T.J. & Howarth, C. (2018). The effect of hyperglycemia on neurovascular coupling and cerebrovascular patterning in zebrafish. Journal of Cerebral Blood Flow & Metabolism 40, 298–313. doi:10.1177/0271678X18810615.CrossRefGoogle ScholarPubMed
Chung, C.C., Pimentel, D., Jor’dan, A.J., Hao, Y., Milberg, W. & Novak, V. (2015). Inflammation-associated declines in cerebral vasoreactivity and cognition in type 2 diabetes. Neurology 85, 450–458.CrossRefGoogle ScholarPubMed
Country, M.W. (2017). Retinal metabolism: A comparative look at energetics in the retina. Brain Research 1672, 50–57.CrossRefGoogle Scholar
Crosby-Nwaobi, R., Sivaprasad, S. & Forbes, A. (2012). A systematic review of the association of diabetic retinopathy and cognitive impairment in people with type 2 diabetes. Diabetes Research and Clinical Practice 96, 101–110.CrossRefGoogle ScholarPubMed
Curtis, T.M., Gardiner, T.A. & Stitt, A.W. (2009). Microvascular lesions of diabetic retinopathy: Clues towards understanding pathogenesis? Eye 23, 1496–1508.CrossRefGoogle ScholarPubMed
de Gooyer, T.E., Stevenson, K.A., Humphries, P., Simpson, D.A., Gardiner, T.A. & Stitt, A.W. (2006). Retinopathy is reduced during experimental diabetes in a mouse model of outer retinal degeneration. Investigative Ophthalmology & Visual Science 47, 5561–5568.CrossRefGoogle Scholar
Dean, F.M., Arden, G.B. & Dornhorst, A. (1997). Partial reversal of protan and tritan colour defects with inhaled oxygen in insulin dependent diabetic subjects. British Journal of Ophthalmology 81, 27–30.CrossRefGoogle ScholarPubMed
Ding, J., Strachan, M.W., Fowkes, F.G., Wong, T.Y., Macgillivray, T.J., Patton, N., Gardiner, T.A., Deary, I.J. & Price, J.F. (2011). Association of retinal arteriolar dilatation with lower verbal memory: The Edinburgh Type 2 Diabetes Study. Diabetologia 54, 1653–1662.CrossRefGoogle ScholarPubMed
Duarte, J.V., Pereira, J.M., Quendera, B., Raimundo, M., Moreno, C., Gomes, L., Carrilho, F. & Castelo-Branco, M. (2015). Early disrupted neurovascular coupling and changed event level hemodynamic response function in type 2 diabetes: An fMRI study. Journal of Cerebral Blood Flow & Metabolism 35, 1671–1680.CrossRefGoogle ScholarPubMed
Dunn, K.M. & Nelson, M.T. (2010). Potassium channels and neurovascular coupling. Circulation Journal 74, 608–616.CrossRefGoogle ScholarPubMed
Fallon, T.J., Maxwell, D. & Kohner, E.M. (1985). Retinal vascular autoregulation in conditions of hyperoxia and hypoxia using the blue field entoptic phenomenon. Ophthalmology 92, 701–705.CrossRefGoogle ScholarPubMed
Fondi, K., Wozniak, P.A., Howorka, K., Bata, A.M., Aschinger, G.C., Popa-Cherecheanu, A., Witkowska, K.J., Hommer, A., Schmidl, D., Werkmeister, R.M., Garhöfer, G. & Schmetterer, L. (2017). Retinal oxygen extraction in individuals with type 1 diabetes with no or mild diabetic retinopathy. Diabetologia 60, 1534–1540.CrossRefGoogle ScholarPubMed
Garhofer, G., Zawinka, C., Resch, H., Huemer, K.H., Dorner, G.T. & Schmetterer, L. (2004a). Diffuse luminance flicker increases blood flow in major retinal arteries and veins. Vision Research 44, 833–838.CrossRefGoogle Scholar
Garhofer, G., Zawinka, C., Resch, H., Kothy, P., Schmetterer, L. & Dorner, G.T. (2004b). Reduced response of retinal vessel diameters to flicker stimulation in patients with diabetes. British Journal of Ophthalmology 88, 887–891.CrossRefGoogle Scholar
Grunwald, J.E., Riva, C.E., Baine, J. & Brucker, A.J. (1992). Total retinal volumetric blood flow rate in diabetic patients with poor glycemic control. Investigative Ophthalmology & Visual Science 33, 356–363.Google ScholarPubMed
Hall, C.N., Reynell, C., Gesslein, B., Hamilton, N.B., Mishra, A., Sutherland, B.A., O’Farrell, F.M., Buchan, A.M., Lauritzen, M. & Attwell, D. (2014). Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508, 55–60.CrossRefGoogle ScholarPubMed
Harris, A., Arend, O., Danis, R.P., Evans, D., Wolf, S. & Martin, B.J. (1996). Hyperoxia improves contrast sensitivity in early diabetic retinopathy. British Journal of Ophthalmology 80, 209–213.CrossRefGoogle ScholarPubMed
Hu, B., Yan, L.F., Sun, Q., Yu, Y., Zhang, J., Dai, Y.J., Yang, Y., Hu, Y.C., Nan, H.Y., Zhang, X., Heng, C.N., Hou, J.F., Liu, Q.Q., Shao, C.H., Li, F., Zhou, K.X., Guo, H., Cui, G.B. & Wang, W. (2019). Disturbed neurovascular coupling in type 2 diabetes mellitus patients: Evidence from a comprehensive fMRI analysis. NeuroImage: Clinical 22, 101802.CrossRefGoogle ScholarPubMed
Hugenschmidt, C.E., Lovato, J.F., Ambrosius, W.T., Bryan, R.N., Gerstein, H.C., Horowitz, K.R., Launer, L.J., Lazar, R.M., Murray, A.M., Chew, E.Y., Danis, R.P., Williamson, J.D., Miller, M.E. & Ding, J. (2014). The cross-sectional and longitudinal associations of diabetic retinopathy with cognitive function and brain MRI findings: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care 37, 3244–3252.CrossRefGoogle ScholarPubMed
Kelly-Cobbs, A.I., Prakash, R., Coucha, M., Knight, R.A., Li, W., Ogbi, S.N., Johnson, M. & Ergul, A. (2012). Cerebral myogenic reactivity and blood flow in type 2 diabetic rats: Role of peroxynitrite in hypoxia-mediated loss of myogenic tone. The Journal of Pharmacology and Experimental Therapeutics 342, 407–415.CrossRefGoogle ScholarPubMed
Kern, T.S. & Engerman, R.L. (2001). Pharmacological inhibition of diabetic retinopathy: Aminoguanidine and aspirin. Diabetes 50, 1636–1642.CrossRefGoogle ScholarPubMed
Kern, T.S., Tang, J., Mizutani, M., Kowluru, R.A., Nagaraj, R.H., Romeo, G., Podesta, F. & Lorenzi, M. (2000). Response of capillary cell death to aminoguanidine predicts the development of retinopathy: Comparison of diabetes and galactosemia. Investigative Ophthalmology & Visual Science 41, 3972–3978.Google ScholarPubMed
Kornfield, T.E. & Newman, E.A. (2014). Regulation of blood flow in the retinal trilaminar vascular network. The Journal of Neuroscience 34, 11504–11513.CrossRefGoogle ScholarPubMed
Kowluru, R.A., Engerman, R.L. & Kern, T.S. (2000). Abnormalities of retinal metabolism in diabetes or experimental galactosemia VIII. Prevention by aminoguanidine. Current Eye Research 21, 814–819.CrossRefGoogle ScholarPubMed
Kur, J., Burian, M.A. & Newman, E.A. (2016). Light adaptation does not prevent early retinal abnormalities in diabetic rats. Scientific Reports 6:21075.CrossRefGoogle Scholar
Kur, J., Newman, E.A. & Chan-Ling, T. (2012). Cellular and physiological mechanisms underlying blood flow regulation in the retina and choroid in health and disease. Progress in Retinal and Eye Research 31, 377–406.CrossRefGoogle ScholarPubMed
Lau, J.C. & Linsenmeier, R.A. (2014). Increased intraretinal PO2 in short-term diabetic rats. Diabetes 63, 4338–4342.CrossRefGoogle ScholarPubMed
Lim, L.S., Ling, L.H., Ong, P.G., Foulds, W., Tai, E.S. & Wong, T.Y. (2017). Dynamic responses in retinal vessel caliber with flicker light stimulation and risk of diabetic retinopathy and its progression. Investigative Ophthalmology & Visual Science 58, 2449–2455.CrossRefGoogle ScholarPubMed
Lindauer, U., Megow, D., Matsuda, H. & Dirnagl, U. (1999). Nitric oxide: A modulator, but not a mediator, of neurovascular coupling in rat somatosensory cortex. American Journal of Physiology. Heart and Circulatory Physiology 277, H799–811.CrossRefGoogle Scholar
Linsenmeier, R.A., Braun, R.D., McRipley, M.A., Padnick, L.B., Ahmed, J., Hatchell, D.L., McLeod, D.S. & Lutty, G.A. (1998). Retinal hypoxia in long-term diabetic cats. Investigative Ophthalmology & Visual Science 39, 1647–1657.Google ScholarPubMed
Mandecka, A., Dawczynski, J., Blum, M., Muller, N., Kloos, C., Wolf, G., Vilser, W., Hoyer, H. & Muller, U.A. (2007). Influence of flickering light on the retinal vessels in diabetic patients. Diabetes Care 30, 3048–3052.CrossRefGoogle ScholarPubMed
Metea, M.R., Kofuji, P. & Newman, E.A. (2007). Neurovascular coupling is not mediated by potassium siphoning from glial cells. The Journal of Neuroscience 27, 2468–2471.CrossRefGoogle Scholar
Metea, M.R. & Newman, E.A. (2006). Glial cells dilate and constrict blood vessels: A mechanism of neurovascular coupling. Journal of Neuroscience 26, 2862–2870.CrossRefGoogle ScholarPubMed
Mishra, A., Hamid, A. & Newman, E.A. (2011). Oxygen modulation of neurovascular coupling in the retina. Proceedings of the National Academy of Sciences of the United States of America 108, 17827–17831.CrossRefGoogle ScholarPubMed
Mishra, A. & Newman, E.A. (2010). Inhibition of inducible nitric oxide synthase reverses the loss of functional hyperemia in diabetic retinopathy. Glia 58, 1996–2004.CrossRefGoogle ScholarPubMed
Mishra, A. & Newman, E.A. (2012). Aminoguanidine reverses the loss of functional hyperemia in a rat model of diabetic retinopathy. Frontiers in Neuroenergetics 3, 10.CrossRefGoogle Scholar
Mishra, A., Reynolds, J.P., Chen, Y., Gourine, A.V., Rusakov, D.A. & Attwell, D. (2016). Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nature Neuroscience 19, 1619–1627.CrossRefGoogle ScholarPubMed
Moheet, A., Mangia, S. & Seaquist, E.R. (2015). Impact of diabetes on cognitive function and brain structure. Annals of the New York Academy of Sciences 1353, 60–71.CrossRefGoogle ScholarPubMed
Movaffaghy, A., Chamot, S.R., Petrig, B.L. & Riva, C.E. (1998). Blood flow in the human optic nerve head during isometric exercise. Experimental Eye Research 67, 561–568.CrossRefGoogle ScholarPubMed
Mozolewska-Piotrowska, K., Nowacka, M., Masiuk, M., Świder, M., Babiak, K., Safranow, K. & Machalińska, A. (2019). Flicker-induced retinal vessels dilatation in diabetic patients without clinically detectable diabetic retinopathy. Klinika Oczna/Acta Ophthalmologica Polonica 2019, 94–99.Google Scholar
Nagayach, A., Patro, N. & Patro, I. (2014). Astrocytic and microglial response in experimentally induced diabetic rat brain. Metabolic Brain Disease 29, 747–761.CrossRefGoogle ScholarPubMed
Newman, E. & Reichenbach, A. (1996). The Muller cell: A functional element of the retina. Trends in Neurosciences 19, 307–312.CrossRefGoogle ScholarPubMed
Newman, E.A. (2015). Glial cell regulation of neuronal activity and blood flow in the retina by release of gliotransmitters. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 370: 20140195.CrossRefGoogle ScholarPubMed
Newman, E.A., Frambach, D.A. & Odette, L.L. (1984). Control of extracellular potassium levels by retinal glial cell K+ siphoning. Science 225, 1174–1175.CrossRefGoogle ScholarPubMed
Nguyen, T.T., Kawasaki, R., Kreis, A.J., Wang, J.J., Shaw, J., Vilser, W. & Wong, T.Y. (2009). Correlation of light-flicker-induced retinal vasodilation and retinal vascular caliber measurements in diabetes. Investigative Ophthalmology & Visual Science 50, 5609–5613.CrossRefGoogle ScholarPubMed
Nippert, A.R., Mishra, A., and Newman, E.A. (2018) Keeping the brain well fed: the role of capillaries and arterioles in orchestrating functional hyperemia. Neuron 99:248–250.CrossRefGoogle ScholarPubMed
Pemp, B., Garhofer, G., Weigert, G., Karl, K., Resch, H., Wolzt, M. & Schmetterer, L. (2009). Reduced retinal vessel response to flicker stimulation but not to exogenous nitric oxide in type 1 diabetes. Investigative Ophthalmology & Visual Science 50, 4029–4032.CrossRefGoogle Scholar
Pemp, B. & Schmetterer, L. (2008). Ocular blood flow in diabetes and age-related macular degeneration. Canadian Journal of Ophthalmology 43, 295–301.CrossRefGoogle ScholarPubMed
Polak, K., Schmetterer, L. & Riva, C.E. (2002). Influence of flicker frequency on flicker-induced changes of retinal vessel diameter. Investigative Ophthalmology & Visual Science 43, 2721–2726.Google ScholarPubMed
Riva, C.E., Logean, E. & Falsini, B. (2005). Visually evoked hemodynamical response and assessment of neurovascular coupling in the optic nerve and retina. Progress in Retinal and Eye Research 24, 183–215.CrossRefGoogle ScholarPubMed
Riva, C.E., Sinclair, S.H. & Grunwald, J.E. (1981). Autoregulation of retinal circulation in response to decrease of perfusion pressure. Investigative Ophthalmology & Visual Science 21(1 Pt 1), 34–38.Google ScholarPubMed
Sivaprasad, S. & Arden, G. (2016). Spare the rods and spoil the retina: Revisited. Eye 30, 189–192.CrossRefGoogle ScholarPubMed
Sivaprasad, S., Vasconcelos, J.C., Prevost, A.T., Holmes, H., Hykin, P., George, S., Murphy, C., Kelly, J., Arden, G.B. & Grp, C.S. (2018). Clinical efficacy and safety of a light mask for prevention of dark adaptation in treating and preventing progression of early diabetic macular oedema at 24 months (CLEOPATRA): A multicentre, phase 3, randomised controlled trial. Lancet Diabetes & Endocrinology 6, 382–391.CrossRefGoogle ScholarPubMed
Song, D., Yao, R. & Pang, C.C. (2008). Altered vasodilator role of nitric oxide synthase in the pancreas, heart and brain of rats with spontaneous type 2 diabetes. European Journal of Pharmacology 591, 177–181.CrossRefGoogle ScholarPubMed
Vetri, F., Xu, H., Paisansathan, C. & Pelligrino, D.A. (2012). Impairment of neurovascular coupling in type 1 diabetes mellitus in rats is linked to PKC modulation of BK(Ca) and Kir channels. American Journal of Physiology. Heart and Circulatory Physiology 302, H1274–1284.CrossRefGoogle ScholarPubMed
Wanek, J., Teng, P.Y., Blair, N.P. & Shahidi, M. (2014). Inner retinal oxygen delivery and metabolism in streptozotocin diabetic rats. Investigative Ophthalmology & Visual Science 55, 1588–1593.CrossRefGoogle ScholarPubMed
Wong, R.H., Raederstorff, D. & Howe, P.R. (2016). Acute resveratrol consumption improves neurovascular coupling capacity in adults with type 2 diabetes mellitus. Nutrients 8, 425.CrossRefGoogle ScholarPubMed
Wright, W.S., McElhatten, R.M. & Harris, N.R. (2011). Increase in retinal hypoxia-inducible factor-2a, but not hypoxia, early in the progression of diabetes in the rat. Experimental Eye Research 93, 437–441.CrossRefGoogle Scholar