Hostname: page-component-586b7cd67f-rcrh6 Total loading time: 0 Render date: 2024-11-20T06:54:35.358Z Has data issue: false hasContentIssue false
  • English
  • Français

Of neurons and pericytes: The neuro-vascular approach to diabetic retinopathy

Published online by Cambridge University Press:  11 August 2020

Cyril G. Eleftheriou ,
Elena Ivanova  and
Botir T. Sagdullaev
Cyril G. Eleftheriou
Affiliation:
Burke Neurological Institute, White Plains, New York
Elena Ivanova
Affiliation:
Burke Neurological Institute, White Plains, New York
Botir T. Sagdullaev*
Affiliation:
Burke Neurological Institute, White Plains, New York Department of Ophthalmology, Weill Cornell Medicine, New York, New York
*
*Address correspondence to: Botir T. Sagdullaev E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Diabetic retinopathy (DR) is a frequent complication of diabetes mellitus and an increasingly common cause of visual impairment. Blood vessel damage occurs as the disease progresses, leading to ischemia, neovascularization, blood–retina barrier (BRB) failure and eventual blindness. Although detection and treatment strategies have improved considerably over the past years, there is room for a better understanding of the pathophysiology of the diabetic retina. Indeed, it has been increasingly realized that DR is in fact a disease of the retina’s neurovascular unit (NVU), the multi-cellular framework underlying functional hyperemia, coupling neuronal computations to blood flow. The accumulating evidence reveals that both neurochemical (synapses) and electrical (gap junctions) means of communications between retinal cells are affected at the onset of hyperglycemia, warranting a global assessment of cellular interactions and their role in DR. This is further supported by the recent data showing down-regulation of connexin 43 gap junctions along the vascular relay from capillary to feeding arteriole as one of the earliest indicators of experimental DR, with rippling consequences to the anatomical and physiological integrity of the retina. Here, recent advancements in our knowledge of mechanisms controlling the retinal neurovascular unit will be assessed, along with their implications for future treatment and diagnosis of DR.

Keywords

Diabetic retinopathyblood flowneurovascular unitpericytesvascular relay
Type
Review Article
Information
Visual Neuroscience , Volume 37 , 2020 , E005
Check for updates
Copyright
© The Author(s), 2020. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Agemy, S.A., Scripsema, N.K., Shah, C.M., Chui, T., Garcia, P.M., Lee, J.G., Gentile, R.C., Hsiao, Y.S., Zhou, Q., Ko, T., & Rosen, R.B. (2015). Retinal vascular erfusion density mapping using optical coherence tomography angiography in normals and diabetic retinopathy patients. Retina 35,2353–2363.CrossRefGoogle Scholar
Ambati, J., Chalam, K.V., Chawla, D.K., D’Angio, C.T., Guillet, E.G., Rose, S.J., Vanderlinde, R.E., & Ambati, B.K. (1997). Elevated gamma-aminobutyric acid, glutamate, and vascular endothelial growth factor levels in the vitreous of patients with proliferative diabetic retinopathy. Archives of Ophthalmology 115, 1161–1166.CrossRefGoogle ScholarPubMed
Attwell, D., Mishra, A., Hall, C.N., O’Farrell, F.M., & Dalkara, T. (2016). What is a pericyte? Journal of Cerebral Blood Flow and Metabolism 36,451–455.CrossRefGoogle Scholar
Aung, M.H., Park, H.N., Han, M.K., Obertone, T.S., Abey, J., Aseem, F., Thule, P.M., Iuvone, P.M., & Pardue, M.T. (2014). Dopamine deficiency contributes to early visual dysfunction in a rodent model of type 1 diabetes. Journal of Neuroscience 34, 726–736.CrossRefGoogle Scholar
Barber, A.J., Antonetti, D.A., Kern, T.S., Reiter, C.E., Soans, R.S., Krady, J.K., Levison, S.W., Gardner, T.W., & Bronson, S.K. (2005). The Ins2 Akita mouse as a model of early retinal complications in diabetes. Investigative Ophthalmology and Visual Science 46, 2210–2218.CrossRefGoogle ScholarPubMed
Barber, A.J., Lieth, E., Khin, S.A., Antonetti, D.A., Buchanan, A.G., & Gardner, T.W. (1998). Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. Journal of Clinical Investigation 102, 783–791.CrossRefGoogle ScholarPubMed
Barbour, B., Brew, H., & Attwell, D. (1988). Electrogenic glutamate uptake in glial cells is activated by intracellular potassium. Nature 335, 433–435.CrossRefGoogle ScholarPubMed
Benedito, S., Prieto, D., Nielsen, P.J., & Nyborg, N.C. (1991). Role of the endothelium in acetylcholine-induced relaxation and spontaneous tone of bovine isolated retinal small arteries. Experimental Eye Research 52, 575–579.CrossRefGoogle ScholarPubMed
Berra, A., Ganzinelli, S., Saravia, M., Borda, E., & Sterin-Borda, L. (2005). Inducible nitric oxide synthase subserves cholinergic vasodilation in retina. Visual NeuroscienceVisual Neuroscience 22, 371–377.CrossRefGoogle ScholarPubMed
Bloomfield, S.A. & Volgyi, B. (2009). The diverse functional roles and regulation of neuronal gap junctions in the retina. Nature Reviews Neuroscience 10, 495–506.CrossRefGoogle ScholarPubMed
Bobbie, M.W., Roy, S., Trudeau, K., Munger, S.J., Simon, A.M., & Roy, S. (2010). Reduced connexin 43 expression and its effect on the development of vascular lesions in retinas of diabetic mice. Investigative Ophthalmology and Visual Science 51, 3758–3763.CrossRefGoogle ScholarPubMed
Boyer, D.S., Yoon, Y.H., Belfort, R., Bandello, F., Maturi, R.K., Augustin, A.J., Li, X.Y., Cui, H., Hashad, Y., Whitcup, S.M., & Ozurdex, M.S.G. (2014). Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 121, 1904–1914.CrossRefGoogle ScholarPubMed
Bringmann, A., Grosche, A., Pannicke, T., & Reichenbach, A. (2013). GABA and glutamate uptake and metabolism in retinal glial (Muller) cells. Front Endocrinol (Lausanne) 4, 48.CrossRefGoogle ScholarPubMed
Bruzzone, R., Haefliger, J.A., Gimlich, R.L., & Paul, D.L. (1993). Connexin40, a component of gap junctions in vascular endothelium, is restricted in its ability to interact with other connexins. Molecular Biology of the Cell 4, 7–20.CrossRefGoogle ScholarPubMed
Campochiaro, P.A., Brown, D.M., Pearson, A., Chen, S., Boyer, D., Ruiz-Moreno, J., Garretson, B., Gupta, A., Hariprasad, S.M., Bailey, C., Reichel, E., Soubrane, G., Kapik, B., Billman, K., Kane, F.E., Green, K., & FAME Study Group (2012). Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology 119, 2125–2132.CrossRefGoogle ScholarPubMed
Catalani, E., Cervia, D., Martini, D., Bagnoli, P., Simonetti, E., Timperio, A.M., & Casini, G. (2007). Changes in neuronal response to ischemia in retinas with genetic alterations of somatostatin receptor expression. European Journal of Neuroscience 25, 1447–1459.CrossRefGoogle ScholarPubMed
Elfgang, C., Eckert, R., Lichtenberg-Frate, H., Butterweck, A., Traub, O., Klein, R.A., Hulser, D.F., & Willecke, K. (1995). Specific permeability and selective formation of gap junction channels in connexin-transfected HeLa cells. Journal of Cell Biology 129, 805–817.CrossRefGoogle ScholarPubMed
Famiglietti, E.V. (1983). ‘Starburst’ amacrine cells and cholinergic neurons: mirror-symmetric on and off amacrine cells of rabbit retina. Brain Research 261, 138–144.CrossRefGoogle ScholarPubMed
Feit-Leichman, R.A., Kinouchi, R., Takeda, M., Fan, Z., Mohr, S., Kern, T.S., & Chen, D.F. (2005). Vascular damage in a mouse model of diabetic retinopathy: Relation to neuronal and glial changes. Investigative Ophthalmology and Visual Science 46, 4281–4287.CrossRefGoogle Scholar
Friedrichs, P., Schlotterer, A., Sticht, C., Kolibabka, M., Wohlfart, P., Dietrich, A., Linn, T., Molema, G., & Hammes, H.P. (2017). Hyperglycaemic memory affects the neurovascular unit of the retina in a diabetic mouse model. Diabetologia 60, 1354–1358.CrossRefGoogle Scholar
Furchgott, R.F. & Zawadzki, J.V. (1980). The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288, 373–376.CrossRefGoogle ScholarPubMed
Garhofer, G., Zawinka, C., Resch, H., Kothy, P., Schmetterer, L., & Dorner, G.T. (2004). Reduced response of retinal vessel diameters to flicker stimulation in patients with diabetes. British Journal of Ophthalmology 88, 887–891.CrossRefGoogle ScholarPubMed
Gastinger, M.J., Barber, A.J., Khin, S.A., McRill, C.S., Gardner, T.W., & Marshak, D.W. (2001). Abnormal centrifugal axons in streptozotocin-diabetic rat retinas. Investigative Ophthalmology and Visual Science 42, 2679–2685.Google ScholarPubMed
Gastinger, M.J., Kunselman, A.R., Conboy, E.E., Bronson, S.K., & Barber, A.J. (2008). Dendrite remodeling and other abnormalities in the retinal ganglion cells of Ins2 Akita diabetic mice. Investigative Ophthalmology and Visual Science 49, 2635–2642.CrossRefGoogle ScholarPubMed
Gastinger, M.J., Singh, R.S., & Barber, A.J. (2006). Loss of cholinergic and dopaminergic amacrine cells in streptozotocin-diabetic rat and Ins2 Akita-diabetic mouse retinas. Investigative Ophthalmology and Visual Science 47, 3143–3150.CrossRefGoogle ScholarPubMed
Gericke, A., Sniatecki, J.J., Goloborodko, E., Steege, A., Zavaritskaya, O., Vetter, J.M., Grus, F.H., Patzak, A., Wess, J., & Pfeiffer, N. (2011). Identification of the muscarinic acetylcholine receptor subtype mediating cholinergic vasodilation in murine retinal arterioles. Investigative Ophthalmology and Visual Science 52, 7479–7484.CrossRefGoogle ScholarPubMed
Gowda, K., Zinnanti, W.J., & LaNoue, K.F. (2011). The influence of diabetes on glutamate metabolism in retinas. Journal of Neurochemistry 117, 309–320.CrossRefGoogle ScholarPubMed
Grubb, S., Cai, C., Hald, B.O., Khennouf, L., Murmu, R.P., Jensen, A.G.K., Fordsmann, J., Zambach, S., & Lauritzen, M. (2020). Precapillary sphincters maintain perfusion in the cerebral cortex. Nature Communications 11, 395.CrossRefGoogle ScholarPubMed
Guthrie, M.J., Osswald, C.R., & Kang-Mieler, J.J. (2014). Inverse relationship between the intraretinal concentration of bioavailable nitric oxide and blood glucose in early experimental diabetic retinopathy. Investigative Ophthalmology and Visual Science 56, 37–44.CrossRefGoogle ScholarPubMed
Hall, CN, Reynell, C, Gesslein, B, Hamilton, NB, Mishra, A, Sutherland, BA, O’Farrell, FM, Buchan, AM, Lauritzen, M, Attwell, D. (2014) Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508, 55–60 (2014).CrossRefGoogle ScholarPubMed
Hayden, S.A., Mills, J.W., & Masland, R.M. (1980). Acetylcholine synthesis by displaced amacrine cells. Science 210, 435–437.CrossRefGoogle ScholarPubMed
Horio, N., Clermont, A.C., Abiko, A., Abiko, T., Shoelson, B.D., Bursell, S.E., & Feener, E.P. (2004). Angiotensin AT(1) receptor antagonism normalizes retinal blood flow and acetylcholine-induced vasodilatation in normotensive diabetic rats. Diabetologia 47, 113–123.CrossRefGoogle ScholarPubMed
Iadecola, C. (2017). The neurovascular unit coming of age: A journey through neurovascular coupling in health and disease. Neuron 96, 17–42.CrossRefGoogle ScholarPubMed
Ishikawa, A., Ishiguro, S., & Tamai, M. (1996). Accumulation of gamma-aminobutyric acid in diabetic rat retinal Muller cells evidenced by electron microscopic immunocytochemistry. Current Eye Research 15, 958–964.CrossRefGoogle ScholarPubMed
Ivanova, E., Kovacs-Oller, T., & Sagdullaev, B.T. (2017). Vascular pericyte impairment and Connexin43 gap junction deficit contribute to vasomotor decline in diabetic retinopathy. Journal of Neuroscience 37, 7580–7594.CrossRefGoogle ScholarPubMed
Ivanova, E., Kovacs-Oller, T., & Sagdullaev, B.T. (2019). Domain-specific distribution of gap junctions defines cellular coupling to establish a vascular relay in the retina. Journal of Comparative Neurology 527, 2675–2693.CrossRefGoogle ScholarPubMed
Ivanova, E., Toychiev, A.H., Yee, C.W., & Sagdullaev, B.T. (2014). Intersublaminar vascular plexus: The correlation of retinal blood vessels with functional sublaminae of the inner plexiform layer. Investigative Ophthalmology and Visual Science 55, 78–86.CrossRefGoogle ScholarPubMed
Ivanova, E., Yee, C.W., & Sagdullaev, B.T. (2016). Disruption in dopaminergic innervation during photoreceptor degeneration. Journal of Comparative Neurology 524, 1208–1221.CrossRefGoogle ScholarPubMed
Jing, M., Zhang, P., Wang, G., Feng, J., Mesik, L., Zeng, J., Jiang, H., Wang, S., Looby, J.C., Guagliardo, N.A., Langma, L.W., Lu, J., Zuo, Y., Talmage, D.A., Role, L.W., Barrett, P.Q., Zhang, L.I., Luo, M., Song, Y., Zhu, J.J., & Li, Y. (2018). A genetically encoded fluorescent acetylcholine indicator for in vitro and in vivo studies. Nature Biotechnology 36, 726–737.CrossRefGoogle ScholarPubMed
Kern, T.S. & Barber, A.J. (2008). Retinal ganglion cells in diabetes. Journal of Physiology 586, 4401–4408.CrossRefGoogle ScholarPubMed
Kim, D., Mouritzen, U., Larsen, B.D., & Roy, S. (2018). Inhibition of Cx43 gap junction uncoupling prevents high glucose-induced apoptosis and reduces excess cell monolayer permeability in retinal vascular endothelial cells. Experimental Eye Research 173, 85–90.CrossRefGoogle ScholarPubMed
Kim, M.K., Aung, M.H., Mees, L., Olson, D.E., Pozdeyev, N., Iuvone, P.M., Thule, P.M., & Pardue, M.T. (2018). Dopamine deficiency mediates early rod-driven NNER retinal dysfunction in diabetic mice. Investigative Ophthalmology and Visual Science 59, 572–581.CrossRefGoogle Scholar
Kornfield, T.E. & Newman, E.A. (2014). Regulation of blood flow in the retinal trilaminar vascular network. Journal of Neuroscience 34, 11504–11513.CrossRefGoogle ScholarPubMed
Koulen, P. (1997). Vesicular acetylcholine transporter (VAChT): A cellular marker in rat retinal development. NeuroReport 8, 2845–2848.CrossRefGoogle ScholarPubMed
Kovacs-Oller, T., Ivanova, E., Bianchimano, P., & Sagdullaev, B.T. (2020). The pericyte connectome: spatial precision of neurovascular coupling is driven by selective connectivity maps of pericytes and endothelial cells and is disrupted in diabetes Cell Discovery; 6:39. doi: 10.1038/s41421-020-0180-0.CrossRefGoogle Scholar
Krady, J.K., Basu, A., Allen, C.M., Xu, Y., LaNoue, K.F., Gardner, T.W., & Levison, S.W. (2005). Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes 54, 1559–1565.CrossRefGoogle Scholar
Kusari, J., Zhou, S., Padillo, E., Clarke, K.G., & Gil, D.W. (2007). Effect of memantine on neuroretinal function and retinal vascular changes of streptozotocin-induced diabetic rats. Investigative Ophthalmology and Visual Science 48, 5152–5159.CrossRefGoogle ScholarPubMed
Lammer, J., Prager, S.G., Cheney, M.C., Ahmed, A., Radwan, S.H., Burns, S.A., Silva, P.S., & Sun, J.K. (2016). Cone photoreceptor irregularity on adaptive optics scanning laser ophthalmoscopy correlates with severity of diabetic retinopathy and macular edema. Investigative Ophthalmology and Visual Science 57, 6624–6632.CrossRefGoogle ScholarPubMed
Lee, T.S., Saltsman, K.A., Ohashi, H., & King, G.L. (1989). Activation of protein kinase C by elevation of glucose concentration: Proposal for a mechanism in the development of diabetic vascular complications. Proceedings of the National Academy of Sciences of the United States of America 86, 5141–5145.CrossRefGoogle ScholarPubMed
Li, Q. & Puro, D.G. (2002). Diabetes-induced dysfunction of the glutamate transporter in retinal Muller cells. Investigative Ophthalmology and Visual Science 43, 3109–3116.Google ScholarPubMed
Lieth, E., Barber, A.J., Xu, B., Dice, C., Ratz, M.J., Tanase, D., & Strother, J.M. (1998). Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy. Penn State Retina Research Group. Diabetes 47, 815–820.CrossRefGoogle ScholarPubMed
Lieth, E., LaNoue, K.F., Antonetti, D.A., & Ratz, M. (2000). Diabetes reduces glutamate oxidation and glutamine synthesis in the retina. The Penn State Retina Research Group. Experimental Eye Research 70, 723–730.CrossRefGoogle ScholarPubMed
Looft-Wilson, R.C., Billaud, M., Johnstone, S.R., Straub, A.C., & Isakson, B.E. (2012). Interaction between nitric oxide signaling and gap junctions: Effects on vascular function. Biochimica et Biophysica Acta 1818, 1895–1902.CrossRefGoogle ScholarPubMed
Lukasiewicz, P.D., Eggers, E.D., Sagdullaev, B.T., & McCall, M.A. (2004). GABAC receptor-mediated inhibition in the retina. Vision Research 44, 3289–3296.CrossRefGoogle 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
Masland, R.H. (2001). The fundamental plan of the retina. Nature Neuroscience 4, 877–886.CrossRefGoogle ScholarPubMed
Masland, R.H. & Livingstone, C.J. (1976). Effect of stimulation with light on synthesis and release of acetylcholine by an isolated mammalian retina. Journal of Neurophysiology 39, 1210–1219.CrossRefGoogle ScholarPubMed
Moore-Dotson, J.M., Beckman, J.J., Mazade, R.E., Hoon, M., Bernstein, A.S., Romero-Aleshire, M.J., Brooks, H.L., & Eggers, E.D. (2016). Early retinal neuronal dysfunction in diabetic mice: Reduced light-evoked inhibition increases rod pathway signaling . Investigative Ophthalmology and Visual Science 57, 1418–1430.CrossRefGoogle ScholarPubMed
Mutchler, S.M. & Straub, A.C. (2015). Compartmentalized nitric oxide signaling in the resistance vasculature. Nitric Oxide 49, 8–15.CrossRefGoogle ScholarPubMed
Nakai, K., Naka, Y., Yokote, H., Ikatura, T., Imai, H., Komai, N., & Maeda, T. (1989). Vascular "sphincter" and microangioarchitecture in the central nervous system: Constriction of intraparenchymal blood vessels following a treatment of vasoconstrictive neurotransmitter. Scanning Microscopy 3, 337–341.Google ScholarPubMed
Nakaizumi, A., Zhang, T., & Puro, D.G. (2012). The electrotonic architecture of the retinal microvasculature: Diabetes-induced alteration. Neurochemistry International 61, 948–953.CrossRefGoogle ScholarPubMed
Nakazawa, T., Kaneko, Y., Mori, A., Saito, M., Sakamoto, K., Nakahara, T., & Ishii, K. (2007). Attenuation of nitric oxide- and prostaglandin-independent vasodilation of retinal arterioles induced by acetylcholine in streptozotocin-treated rats. Vascular Pharmacology 46, 153–159.CrossRefGoogle ScholarPubMed
Nelson, A.R., Sagare, M.A., Wang, Y., Kisler, K., Zhao, Z., & Zlokovic, B.V. (2020). Channelrhodopsin excitation contracts brain pericytes and reduces blood flow in the aging mouse brain in vivo. Frontiers in Aging Neuroscience 12, 108.CrossRefGoogle ScholarPubMed
Newman, E.A. (2013) Functional hyperemia and mechanisms of neurovascular coupling in the retinal vasculature. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 33, 1685–1695.CrossRefGoogle ScholarPubMed
Noonan, JE, Lamoureux, EL, Sarossy, M. (2015) Neuronal activity-dependent regulation of retinal blood flow. Clin Exp Ophthalmol. 43(7):673-82.CrossRefGoogle ScholarPubMed
O’Brien, J. & Bloomfield, S.A. (2018). Plasticity of retinal gap junctions: Roles in synaptic physiology and disease. Annual Review of Vision Science 4, 79–100.CrossRefGoogle ScholarPubMed
Oku, H., Kodama, T., Sakagami, K., & Puro, D.G. (2001). Diabetes-induced disruption of gap junction pathways within the retinal microvasculature. Investigative Ophthalmology and Visual Science 42, 1915–1920.Google ScholarPubMed
Palmer, R.M., Ferrige, A.G., & Moncada, S. (1987). Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327, 524–526.CrossRefGoogle ScholarPubMed
Peppiatt, C.M., Howarth, C., Mobbs, P., & Attwell, D. (2006). Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700–704.CrossRefGoogle ScholarPubMed
Poitry, S., Poitry-Yamate, C., Ueberfeld, J., MacLeish, P.R., & Tsacopoulos, M. (2000). Mechanisms of glutamate metabolic signaling in retinal glial (Muller) cells. Journal of Neuroscience 20, 1809–1821.CrossRefGoogle ScholarPubMed
Puro, D.G. (2012). Retinovascular physiology and pathophysiology: New experimental approach/new insights. Progress in Retinal and Eye Research 31, 258–270.CrossRefGoogle ScholarPubMed
Ramsey, D.J., Ripps, H., & Qian, H. (2007). Streptozotocin-induced diabetes modulates GABA receptor activity of rat retinal neurons. Experimental Eye Research 85, 413–422.CrossRefGoogle 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
Rubsam, A., Parikh, S., & Fort, P.E. (2018). Role of Inflammation in diabetic retinopathy. International Journal of Molecular Sciences 19).CrossRefGoogle ScholarPubMed
Rungta, R.L., Chaigneau, E., Osmanski, B.F., & Charpak, S. (2018). Vascular compartmentalization of functional hyperemia from the Synapse to the Pia. Neuron 99, 362–375e364.CrossRefGoogle ScholarPubMed
Sakagami, K., Kawamura, H., Wu, D.M., & Puro, D.G. (2001). Nitric oxide/cGMP-induced inhibition of calcium and chloride currents in retinal pericytes. Microvascular Research 62, 196–203.CrossRefGoogle ScholarPubMed
Sato, T., Haimovici, R., Kao, R., Li, A.F., & Roy, S. (2002). Downregulation of connexin 43 expression by high glucose reduces gap junction activity in microvascular endothelial cells. Diabetes 51, 1565–1571.CrossRefGoogle ScholarPubMed
Schonfelder, U., Hofer, A., Paul, M., & Funk, R.H. (1998). In situ observation of living pericytes in rat retinal capillaries. Microvascular Research 56, 22–29.CrossRefGoogle ScholarPubMed
Sethuramanujam, S., Matsumoto, A., McIntosh, J.M., Jing, M., Li, Y., Berson, D., Yonehara, K., & Awatramani, G.B. (2020). Rapid ‘multi-directed’ cholinergic transmission at central synapses. bioRxiv: 2020.2004.2018.048330.Google Scholar
Shibata, M., Nakaizumi, A., & Puro, D.G. (2019). Electrotonic transmission in the retinal vasculature: Inhibitory role of the diabetes/VEGF/aPKC pathway. Physiological Reports 7, e14095.CrossRefGoogle ScholarPubMed
Simo, R., Hernandez, C.R., & European Consortium for the Early Treatment of Diabetic (2014). Neurodegeneration in the diabetic eye: New insights and therapeutic perspectives. Trends in Endocrinology Metabolism 25, 23–33.CrossRefGoogle ScholarPubMed
Smith, S.B. (2002). Diabetic retinopathy and the NMDA receptor. Drug News and Perspectives 15, 226–232.CrossRefGoogle ScholarPubMed
Srinivas, S., Tan, O., Nittala, M.G., Wu, J.L., Fawzi, A.A., Huang, D., & Sadda, S.R. (2017). Assessment of retinal blood flow in diabetic retinopathy using Doppler Fourier-domain optical coherence tomography. Retina 37, 2001–2007.CrossRefGoogle ScholarPubMed
Straub, A.C., Billaud, M., Johnstone, S.R., Best, A.K., Yemen, S., Dwyer, S.T., Looft-Wilson, R., Lysiak, J.J., Gaston, B., Palmer, L., & Isakson, B.E. (2011). Compartmentalized connexin 43 s-nitrosylation/denitrosylation regulates heterocellular communication in the vessel wall. Arteriosclerosis Thrombosis and Vascular Biology 31, 399–407.CrossRefGoogle ScholarPubMed
Takeo-Goto, S., Doi, M., Ma, N., Goto, R., Semba, R., & Uji, Y. (2002). Immunohistochemical localization of amino acids in the diabetic retina of Goto-Kakizaki rats. Ophthalmology Research 34, 139–145.CrossRefGoogle ScholarPubMed
Wang, J., O’Sullivan, M.L., Mukherjee, D., Punal, V.M., Farsiu, S., & Kay, J.N. (2017). Anatomy and spatial organization of Muller glia in mouse retina. Journal of Comparative Neurology 525, 1759–1777.CrossRefGoogle ScholarPubMed
Wang, Z., Yadav, A.S., Leskova, W., & Harris, N.R. (2010). Attenuation of streptozotocin-induced microvascular changes in the mouse retina with the endothelin receptor A antagonist atrasentan. Experimental Eye Research 91, 670–675.CrossRefGoogle ScholarPubMed
Wells, J.A., Glassman, A.R., Ayala, A.R., Jampol, L.M., Bressler, N.M., Bressler, S.B., Brucker, A.J., Ferris, F.L., Hampton, G.R., Jhaveri, C., Melia, M., Beck, R.W., & Diabetic Retinopathy Clinical Research Network (2016). Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: Two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology 123, 1351–1359.CrossRefGoogle ScholarPubMed
Williams, B., & Schrier, R.W. (1993). Glucose-induced protein kinase C activity regulates arachidonic acid release and eicosanoid production by cultured glomerular mesangial cells. Journal of Clinical Investigation 92, 2889–2896.CrossRefGoogle ScholarPubMed
Witkovsky, P. (2004). Dopamine and retinal function. Documenta Ophthalmologica 108, 17–40.CrossRefGoogle ScholarPubMed
Wu, D.M., Kawamura, H., Sakagami, K., Kobayashi, M., & Puro, D.G. (2003). Cholinergic regulation of pericyte-containing retinal microvessels. American Journal of Physiology: Heart and Circulatory Physiology 284 ,H2083–H2090.Google ScholarPubMed
Yu, PK, Yu, DY, Cringle, SJ, Su, EN (2004) Tetrahydrobiopterin reverses the impairment of acetylcholine-induced vasodilatation in diabetic ocular microvasculature. J Ocul Pharmacol Ther 17:123–129.CrossRefGoogle Scholar