Associations of retinal neurovascular dysfunction with inner retinal layer thickness in non-proliferative diabetic retinopathy.
Diabetes mellitus
Diabetic retinopathy
Dynamic vessel analysis
Neurovascular coupling
Optical coherence tomography
Retinal neurodegeneration
Journal
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie
ISSN: 1435-702X
Titre abrégé: Graefes Arch Clin Exp Ophthalmol
Pays: Germany
ID NLM: 8205248
Informations de publication
Date de publication:
15 Jun 2024
15 Jun 2024
Historique:
received:
06
03
2024
accepted:
07
06
2024
revised:
04
06
2024
medline:
15
6
2024
pubmed:
15
6
2024
entrez:
15
6
2024
Statut:
aheadofprint
Résumé
Neurovascular coupling impairment and inner retinal layer thinning are early detectable retinal changes in diabetes, and both worsen during progression of diabetic retinopathy (DR). However, direct interactions between these features have not been investigated so far. Therefore, we aimed to analyze associations between the retinal functional hyperemic response to light stimulation and the thickness of individual neuroretinal layers in eyes with early non-proliferative DR. Thirty patients with type 1 diabetes featuring mild (n = 15) or moderate (n = 15) non-proliferative DR and 14 healthy subjects were included in this cross-sectional study. Retinal vessel diameters were measured before and during illumination with flickering light using a dynamic vessel analyzer. Individual layer thickness in the macula was analyzed from spectral domain optical coherence tomography. Flicker light-induced vessel dilation was significantly reduced in patients compared to healthy controls (veins: 3.0% vs. 6.1%, p < 0.001; arteries: 1.3% vs. 5.1%, p = 0.005). Univariately, the response in retinal veins of diabetes patients correlated significantly with ganglion cell layer (GCL) thickness (r = 0.46, p = 0.010), and negatively with hemoglobin A1c (HbA1c) levels (r=-0.41, p = 0.023) and age (r=-0.38, p = 0.037), but not with baseline diameters, glucose levels, or diabetes duration. In a multiple regression model only GCL thickness (p = 0.017, β = 0.42) and HbA1c (p = 0.045, β=-0.35) remained significantly associated with the vascular flicker light response. The results indicate that thinner GCL and worse glycemic control both contribute to reduced retinal neurovascular coupling in patients with clinical signs of DR. Progression of neurovascular dysfunction in DR might be related to structural degeneration of the neurovascular complex in the inner retina.
Identifiants
pubmed: 38878068
doi: 10.1007/s00417-024-06552-4
pii: 10.1007/s00417-024-06552-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Barber AJ, Gardner TW, Abcouwer SF (2011) The significance of vascular and neural apoptosis to the pathology of diabetic retinopathy. Invest Ophthalmol Vis Sci 52(2):1156–1163. https://doi.org/10.1167/iovs.10-6293
doi: 10.1167/iovs.10-6293
pubmed: 21357409
pmcid: 3053099
Biallosterski C, van Velthoven ME, Michels RP, Schlingemann RO, DeVries JH, Verbraak FD (2007) Decreased optical coherence tomography-measured pericentral retinal thickness in patients with diabetes mellitus type 1 with minimal diabetic retinopathy. Br J Ophthalmol 91(9):1135–1138. https://doi.org/10.1136/bjo.2006.111534
doi: 10.1136/bjo.2006.111534
pubmed: 17383994
pmcid: 1954913
Oshitari T, Hanawa K, Adachi-Usami E (2009) Changes of macular and RNFL thicknesses measured by Stratus OCT in patients with early stage diabetes. Eye 23(4):884–889. https://doi.org/10.1038/eye.2008.119
doi: 10.1038/eye.2008.119
pubmed: 18437178
Simó R, Hernández C, European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) (2012) Neurodegeneration is an early event in diabetic retinopathy: therapeutic implications. Br J Ophthalmol 96(10):1285–1290. https://doi.org/10.1136/bjophthalmol-2012-302005
doi: 10.1136/bjophthalmol-2012-302005
pubmed: 22887976
De Clerck EE, Schouten JS, Berendschot TT, Kessels AG, Nuijts RM, Beckers HJ, Schram MT, Stehouwer CD, Webers CA (2015) New ophthalmologic imaging techniques for detection and monitoring of neurodegenerative changes in diabetes: a systematic review. Lancet Diabetes Endocrinol 3(8):653–663. https://doi.org/10.1016/S2213-8587(15)00136-9
doi: 10.1016/S2213-8587(15)00136-9
pubmed: 26184671
Sohn EH, van Dijk HW, Jiao C, Kok PH, Jeong W, Demirkaya N, Garmager A, Wit F, Kucukevcilioglu M, van Velthoven ME, DeVries JH, Mullins RF, Kuehn MH, Schlingemann RO, Sonka M, Verbraak FD, Abràmoff MD (2016) Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus. Proc Natl Acad Sci U S A 113(19):E2655–2664. https://doi.org/10.1073/pnas.1522014113
doi: 10.1073/pnas.1522014113
pubmed: 27114552
pmcid: 4868487
van Dijk HW, Kok PH, Garvin M, Sonka M, Devries JH, Michels RP, van Velthoven ME, Schlingemann RO, Verbraak FD, Abràmoff MD (2009) Selective loss of inner retinal layer thickness in type 1 diabetic patients with minimal diabetic retinopathy. Invest Ophthalmol Vis Sci 50(7):3404–3409. https://doi.org/10.1167/iovs.08-3143
doi: 10.1167/iovs.08-3143
pubmed: 19151397
Cabrera DeBuc D, Somfai GM (2010) Early detection of retinal thickness changes in diabetes using Optical Coherence Tomography. Med Sci Monit 16(3):MT15–MT21
pubmed: 20190693
van Dijk HW, Verbraak FD, Kok PH, Stehouwer M, Garvin MK, Sonka M, DeVries JH, Schlingemann RO, Abràmoff MD (2012) Early neurodegeneration in the retina of type 2 diabetic patients. Invest Ophthalmol Vis Sci 53(6):2715–2719. https://doi.org/10.1167/iovs.11-8997
doi: 10.1167/iovs.11-8997
pubmed: 22427582
pmcid: 3366721
Chhablani J, Sharma A, Goud A, Peguda HK, Rao HL, Begum VU, Barteselli G (2015) Neurodegeneration in Type 2 Diabetes: Evidence From Spectral-Domain Optical Coherence Tomography. Invest Ophthalmol Vis Sci 56(11):6333–6338. https://doi.org10.1167/iovs.15-17334
Spaide RF (2019) Measurable aspects of the retinal neurovascular unit in diabetes, Glaucoma, and controls. Am J Ophthalmol 207:395–409. https://doi.org/10.1016/j.ajo.2019.04.035
doi: 10.1016/j.ajo.2019.04.035
pubmed: 31078537
Ng DS, Chiang PP, Tan G, Cheung CG, Cheng CY, Cheung CY, Wong TY, Lamoureux EL, Ikram MK (2016) Retinal ganglion cell neuronal damage in diabetes and diabetic retinopathy. Clin Exp Ophthalmol 44(4):243–250. https://doi.org/10.1111/ceo.12724
doi: 10.1111/ceo.12724
pubmed: 26872562
Kim K, Kim ES, Kim DG, Yu SY (2019) Progressive retinal neurodegeneration and microvascular change in diabetic retinopathy: longitudinal study using OCT angiography. Acta Diabetol 56(12):1275–1282. https://doi.org/10.1007/s00592-019-01395-6
doi: 10.1007/s00592-019-01395-6
pubmed: 31401734
Caputo S, Di Leo MA, Falsini B, Ghirlanda G, Porciatti V, Minella A, Greco AV (1990) Evidence for early impairment of macular function with pattern ERG in type I diabetic patients. Diabetes Care 13(4):412–418. https://doi.org/10.2337/diacare.13.4.412
doi: 10.2337/diacare.13.4.412
pubmed: 2318101
Juen S, Kieselbach GF (1990) Electrophysiological changes in juvenile diabetics without retinopathy. Arch Ophthalmol 108(3):372–375. https://doi.org/10.1001/archopht.1990.01070050070033
doi: 10.1001/archopht.1990.01070050070033
pubmed: 2310337
Palmowski AM, Sutter EE, Bearse MA Jr, Fung W (1997) Mapping of retinal function in diabetic retinopathy using the multifocal electroretinogram. Invest Ophthalmol Vis Sci 38(12):2586–2596
pubmed: 9375578
Lopes de Faria JM, Katsumi O, Cagliero E, Nathan D, Hirose T (2001) Neurovisual abnormalities preceding the retinopathy in patients with long-term type 1 diabetes mellitus. Graefes Arch Clin Exp Ophthalmol 239(9):643–648. https://doi.org/10.1007/s004170100268
doi: 10.1007/s004170100268
pubmed: 11688662
Realini T, Lai MQ, Barber L (2004) Impact of diabetes on glaucoma screening using frequency-doubling perimetry. Ophthalmology 111(11):2133–2136. https://doi.org/10.1016/j.ophtha.2004.05.024
doi: 10.1016/j.ophtha.2004.05.024
pubmed: 15522382
Stavrou EP, Wood JM (2005) Central visual field changes using flicker perimetry in type 2 diabetes mellitus. Acta Ophthalmol Scand 83(5):574–580. https://doi.org/10.1111/j.1600-0420.2005.00527.x
doi: 10.1111/j.1600-0420.2005.00527.x
pubmed: 16187995
Gualtieri M, Bandeira M, Hamer RD, Damico FM, Moura AL, Ventura DF (2011) Contrast sensitivity mediated by inferred magno- and parvocellular pathways in type 2 diabetics with and without nonproliferative retinopathy. Invest Ophthalmol Vis Sci 52(2):1151–1155. https://doi.org/10.1167/iovs.09-3705
doi: 10.1167/iovs.09-3705
pubmed: 21051718
Jackson GR, Scott IU, Quillen DA, Walter LE, Gardner TW (2012) Inner retinal visual dysfunction is a sensitive marker of non-proliferative diabetic retinopathy. Br J Ophthalmol 96(5):699–703. https://doi.org/10.1136/bjophthalmol-2011-300467
doi: 10.1136/bjophthalmol-2011-300467
pubmed: 22174096
Zeng Y, Cao D, Yu H, Yang D, Zhuang X, Hu Y, Li J, Yang J, Wu Q, Liu B, Zhang L (2019) Early retinal neurovascular impairment in patients with diabetes without clinically detectable retinopathy. Br J Ophthalmol 103(12):1747–1752. https://doi.org/10.1136/bjophthalmol-2018-313582
doi: 10.1136/bjophthalmol-2018-313582
pubmed: 30674454
Arend O, Wolf S, Remky A, Sponsel WE, Harris A, Bertram B, Reim M (1994) Perifoveal microcirculation with non-insulin-dependent diabetes mellitus. Graefes Arch Clin Exp Ophthalmol 232(4):225–231. https://doi.org/10.1007/BF00184010
doi: 10.1007/BF00184010
pubmed: 8034211
Chua J, Sim R, Tan B, Wong D, Yao X, Liu X, Ting DSW, Schmidl D, Ang M, Garhöfer G, Schmetterer L (2020) Optical coherence Tomography Angiography in Diabetes and Diabetic Retinopathy. J Clin Med 9(6):1723. https://doi.org/10.3390/jcm9061723
doi: 10.3390/jcm9061723
pubmed: 32503234
pmcid: 7357089
Li X, Xie J, Zhang L, Cui Y, Zhang G, Chen X, Wang J, Zhang A, Huang T, Meng Q (2020) Identifying Microvascular and neural parameters related to the severity of Diabetic Retinopathy using Optical Coherence Tomography Angiography. Invest Ophthalmol Vis Sci 61(5):39. https://doi.org/10.1167/iovs.61.5.39
doi: 10.1167/iovs.61.5.39
pubmed: 32441757
pmcid: 7405728
Marques IP, Ferreira S, Santos T, Madeira MH, Santos AR, Mendes L, Lobo C, Cunha-Vaz J (2022) Association between Neurodegeneration and Macular Perfusion in the progression of Diabetic Retinopathy: a 3-Year longitudinal study. Ophthalmologica 245(4):335–341. https://doi.org/10.1159/000522527
doi: 10.1159/000522527
pubmed: 35158351
Sung JY, Lee MW, Lim HB, Ryu CK, Yu HY, Kim JY (2022) The Ganglion Cell-Inner Plexiform Layer Thickness/Vessel density of superficial vascular plexus ratio according to the progression of Diabetic Retinopathy. Invest Ophthalmol Vis Sci 63(6):4. https://doi.org/10.1167/iovs.63.6.4
doi: 10.1167/iovs.63.6.4
pubmed: 35653120
pmcid: 9172016
Sakata K, Funatsu H, Harino S, Noma H, Hori S (2006) Relationship between macular microcirculation and progression of diabetic macular edema. Ophthalmology 113(8):1385–1391. https://doi.org/10.1016/j.ophtha.2006.04.023
doi: 10.1016/j.ophtha.2006.04.023
pubmed: 16877077
Palochak CMA, Lee HE, Song J, Geng A, Linsenmeier RA, Burns SA, Fawzi AA (2019) Retinal blood velocity and Flow in Early Diabetes and Diabetic Retinopathy using adaptive Optics scanning laser Ophthalmoscopy. J Clin Med 8(8):1165. https://doi.org/10.3390/jcm8081165
doi: 10.3390/jcm8081165
pubmed: 31382617
pmcid: 6723736
Pournaras CJ, Rungger-Brändle E, Riva CE, Hardarson SH, Stefansson E (2008) Regulation of retinal blood flow in health and disease. Prog Retin Eye Res 27(3):284–330. https://doi.org/10.1016/j.preteyeres.2008.02.002
doi: 10.1016/j.preteyeres.2008.02.002
pubmed: 18448380
Metea MR, Newman EA (2007) Signalling within the neurovascular unit in the mammalian retina. Exp Physiol 92(4):635–640. https://doi.org/10.1113/expphysiol.2006.036376
doi: 10.1113/expphysiol.2006.036376
pubmed: 17434916
Andreone BJ, Lacoste B, Gu C (2015) Neuronal and vascular interactions. Annu Rev Neurosci 38:25–46. https://doi.org/10.1146/annurev-neuro-071714-033835
doi: 10.1146/annurev-neuro-071714-033835
pubmed: 25782970
pmcid: 5729758
Garhöfer G, Chua J, Tan B, Wong D, Schmidl D, Schmetterer L (2020) Retinal neurovascular coupling in diabetes. J Clin Med 9(9):2829. https://doi.org/10.3390/jcm9092829
doi: 10.3390/jcm9092829
pubmed: 32882896
Dorner GT, Garhöfer G, Huemer KH, Riva CE, Wolzt M, Schmetterer L (2003) Hyperglycemia affects flicker-induced vasodilation in the retina of healthy subjects. Vis Res 43(13):1495–1500. https://doi.org/10.1016/s0042-6989(03)00170-6
doi: 10.1016/s0042-6989(03)00170-6
pubmed: 12767316
Kwan CC, Lee HE, Schwartz G, Fawzi AA (2020) Acute Hyperglycemia reverses neurovascular Coupling during Dark to Light Adaptation in healthy subjects on Optical Coherence Tomography Angiography. Invest Ophthalmol Vis Sci 61(4):38. https://doi.org/10.1167/iovs.61.4.38
doi: 10.1167/iovs.61.4.38
pubmed: 32340033
pmcid: 7401911
Garhöfer G, Zawinka C, Resch H, Kothy P, Schmetterer L, Dorner GT (2004) Reduced response of retinal vessel diameters to flicker stimulation in patients with diabetes. Br J Ophthalmol 88(7):887–891. https://doi.org/10.1136/bjo.2003.033548
doi: 10.1136/bjo.2003.033548
pubmed: 15205231
pmcid: 1772243
Mandecka A, Dawczynski J, Blum M, Müller N, Kloos C, Wolf G, Vilser W, Hoyer H, Müller UA (2007) Influence of flickering light on the retinal vessels in diabetic patients. Diabetes Care 30(12):3048–3052. https://doi.org/10.2337/dc07-0927
doi: 10.2337/dc07-0927
pubmed: 17728481
Zhang YS, Mucollari I, Kwan CC, Dingillo G, Amar J, Schwartz GW, Fawzi AA (2020) Reversed neurovascular coupling on Optical Coherence Tomography Angiography is the earliest detectable abnormality before Clinical Diabetic Retinopathy. J Clin Med 9(11):3523. https://doi.org/10.3390/jcm9113523
doi: 10.3390/jcm9113523
pubmed: 33142724
pmcid: 7692675
Lecleire-Collet A, Audo I, Aout M, Girmens JF, Sofroni R, Erginay A, Le Gargasson JF, Mohand-Saïd S, Meas T, Guillausseau PJ, Vicaut E, Paques M, Massin P (2011) Evaluation of retinal function and flicker light-induced retinal vascular response in normotensive patients with diabetes without retinopathy. Invest Ophthalmol Vis Sci 52(6):2861–2867. https://doi.org/10.1167/iovs.10-5960
doi: 10.1167/iovs.10-5960
pubmed: 21282578
Lasta M, Pemp B, Schmidl D, Boltz A, Kaya S, Palkovits S, Werkmeister R, Howorka K, Popa-Cherecheanu A, Garhöfer G, Schmetterer L (2013) Neurovascular dysfunction precedes neural dysfunction in the retina of patients with type 1 diabetes. Invest Ophthalmol Vis Sci 54(1):842–847. https://doi.org/10.1167/iovs.12-10873
doi: 10.1167/iovs.12-10873
pubmed: 23307962
Nguyen TT, Kawasaki R, Wang JJ, Kreis AJ, Shaw J, Vilser W, Wong TY (2009) Flicker light-induced retinal vasodilation in diabetes and diabetic retinopathy. Diabetes Care 32(11):2075–2080. https://doi.org/10.2337/dc09-0075
doi: 10.2337/dc09-0075
pubmed: 19641162
pmcid: 2768208
Hommer N, Kallab M, Schlatter A, Janku P, Werkmeister RM, Howorka K, Schmidl D, Schmetterer L, Garhöfer G (2022) Neuro-vascular coupling and heart rate variability in patients with type II diabetes at different stages of diabetic retinopathy. Front Med 9:1025853. https://doi.org/10.3389/fmed.2022.1025853
doi: 10.3389/fmed.2022.1025853
Early Treatment Diabetic Retinopathy Study Research Group (1991) Grading diabetic retinopathy from stereoscopic color fundus photographs–an extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology 98(5 Suppl):786–806. https://doi.org/10.1016/S0161-6420(13)38012-9
doi: 10.1016/S0161-6420(13)38012-9
Garhofer G, Bek T, Boehm AG, Gherghel D, Grunwald J, Jeppesen P, Kergoat H, Kotliar K, Lanzl I, Lovasik JV, Nagel E, Vilser W, Orgul S, Schmetterer L, Ocular Blood Flow Research Association (2010) Use of the retinal vessel analyzer in ocular blood flow research. Acta Ophthalmol 88(7):717–722. https://doi.org/10.1111/j.1755-3768.2009.01587.x
doi: 10.1111/j.1755-3768.2009.01587.x
pubmed: 19681764
Castro Lima V, Rodrigues EB, Nunes RP, Sallum JF, Farah ME, Meyer CH (2011) Simultaneous confocal scanning laser ophthalmoscopy combined with high-resolution spectral-domain optical coherence tomography: a review. J Ophthalmol 2011:743670. https://doi.org/10.1155/2011/743670
doi: 10.1155/2011/743670
pubmed: 22132313
pmcid: 3206361
Pemp B, Kardon RH, Kircher K, Pernicka E, Schmidt-Erfurth U, Reitner A (2013) Effectiveness of averaging strategies to reduce variance in retinal nerve fibre layer thickness measurements using spectral-domain optical coherence tomography. Graefes Arch Clin Exp Ophthalmol 251(7):1841–1848. https://doi.org/10.1007/s00417-013-2337-0
doi: 10.1007/s00417-013-2337-0
pubmed: 23589277
Carpineto P, Toto L, Aloia R, Ciciarelli V, Borrelli E, Vitacolonna E, Di Nicola M, Di Antonio L, Mastropasqua R (2016) Neuroretinal alterations in the early stages of diabetic retinopathy in patients with type 2 diabetes mellitus. Eye 30(5):673–679. https://doi.org/10.1038/eye.2016.13
doi: 10.1038/eye.2016.13
pubmed: 26869156
pmcid: 4869127
van de Kreeke JA, Darma S, Chan Pin Yin JMPL, Tan HS, Abramoff MD, Twisk JWR, Verbraak FD (2020) The spatial relation of diabetic retinal neurodegeneration with diabetic retinopathy. PLoS ONE 15(4):e0231552. https://doi.org/10.1371/journal.pone.0231552
doi: 10.1371/journal.pone.0231552
pubmed: 32298369
pmcid: 7161968
Aschauer J, Pollreisz A, Karst S, Hülsmann M, Hajdu D, Datlinger F, Egner B, Kriechbaum K, Pablik E, Schmidt-Erfurth UM (2022) Longitudinal analysis of microvascular perfusion and neurodegenerative changes in early type 2 diabetic retinal disease. Br J Ophthalmol 106(4):528–533. https://doi.org/10.1136/bjophthalmol-2020-317322
doi: 10.1136/bjophthalmol-2020-317322
pubmed: 33293271
Abu-El-Asrar AM, Dralands L, Missotten L, Al-Jadaan IA, Geboes K (2004) Expression of apoptosis markers in the retinas of human subjects with diabetes. Invest Ophthalmol Vis Sci 45(8):2760–2766. https://doi.org/10.1167/iovs.03-1392
doi: 10.1167/iovs.03-1392
pubmed: 15277502
Gastinger MJ, Barber AJ, Khin SA, McRill CS, Gardner TW, Marshak DW (2001) Abnormal centrifugal axons in streptozotocin-diabetic rat retinas. Invest Ophthalmol Vis Sci 42(11):2679–2685
pubmed: 11581216
Gastinger MJ, Singh RS, Barber AJ (2006) Loss of cholinergic and dopaminergic amacrine cells in streptozotocin-diabetic rat and Ins2Akita-diabetic mouse retinas. Invest Ophthalmol Vis Sci 47(7):3143–3150. https://doi.org/10.1167/iovs.05-1376
doi: 10.1167/iovs.05-1376
pubmed: 16799061
Fernandez DC, Pasquini LA, Dorfman D, Aldana Marcos HJ, Rosenstein RE (2012) Early distal axonopathy of the visual pathway in experimental diabetes. Am J Pathol 180(1):303–313. https://doi.org/10.1016/j.ajpath.2011.09.018
doi: 10.1016/j.ajpath.2011.09.018
pubmed: 22079928
pmcid: 3244601
Mandecka A, Dawczynski J, Vilser W, Blum M, Müller N, Kloos C, Wolf G, Müller UA (2009) Abnormal retinal autoregulation is detected by provoked stimulation with flicker light in well-controlled patients with type 1 diabetes without retinopathy. Diabetes Res Clin Pract 86(1):51–55. https://doi.org/10.1016/j.diabres.2009.06.017
doi: 10.1016/j.diabres.2009.06.017
pubmed: 19646772
Patel SR, Bellary S, Qin L, Balanos GM, McIntyre D, Gherghel D (2012) Abnormal retinal vascular reactivity in individuals with impaired glucose tolerance: a preliminary study. Invest Ophthalmol Vis Sci 53(9):5102–5108. https://doi.org/10.1167/iovs.12-9512
doi: 10.1167/iovs.12-9512
pubmed: 22743316
Lim LS, Ling LH, Ong PG, Foulds W, Tai ES, Wong TY (2017) Dynamic responses in Retinal Vessel Caliber with Flicker Light Stimulation and Risk of Diabetic Retinopathy and its progression. Invest Ophthalmol Vis Sci 58(5):2449–2455. https://doi.org/10.1167/iovs.16-21008
doi: 10.1167/iovs.16-21008
pubmed: 28460046
Mishra A, Newman EA (2010) Inhibition of inducible nitric oxide synthase reverses the loss of functional hyperemia in diabetic retinopathy. Glia 58(16):1996–2004. https://doi.org/10.1002/glia.21068
doi: 10.1002/glia.21068
pubmed: 20830810
pmcid: 3206643
Hanaguri J, Yokota H, Watanabe M, Yamagami S, Kushiyama A, Kuo L, Nagaoka T (2021) Retinal blood flow dysregulation precedes neural retinal dysfunction in type 2 diabetic mice. Sci Rep 11(1):18401. https://doi.org/10.1038/s41598-021-97651-3
doi: 10.1038/s41598-021-97651-3
pubmed: 34526573
pmcid: 8443656
Kawasaki A, Otori Y, Barnstable CJ (2000) Müller cell protection of rat retinal ganglion cells from glutamate and nitric oxide neurotoxicity. Invest Ophthalmol Vis Sci 41(11):3444–3450
pubmed: 11006237
Petersen L, Bek T (2016) Preserved pressure autoregulation but disturbed cyclo-oxygenase and nitric Oxide effects on Retinal Arterioles during Acute Hypoxia in Diabetic patients without Retinopathy. Ophthalmologica 235(2):114–120. https://doi.org/10.1159/000443147
doi: 10.1159/000443147
pubmed: 26741496
Honasoge A, Nudleman E, Smith M, Rajagopal R (2019) Emerging insights and interventions for Diabetic Retinopathy. Curr Diab Rep 19(10):100. https://doi.org/10.1007/s11892-019-1218-2
doi: 10.1007/s11892-019-1218-2
pubmed: 31506830
pmcid: 7941754
Nian S, Lo ACY, Mi Y, Ren K, Yang D (2021) Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets. Eye Vis 8(1):15. https://doi.org/10.1186/s40662-021-00239-1
doi: 10.1186/s40662-021-00239-1
Forst T, Michelson G, Ratter F, Weber MM, Anders S, Mitry M, Wilhelm B, Pfützner A (2012) Addition of liraglutide in patients with type 2 diabetes well controlled on metformin monotherapy improves several markers of vascular function. Diabet Med 29(9):1115–1118. https://doi.org/10.1111/j.1464-5491.2012.03589.x
doi: 10.1111/j.1464-5491.2012.03589.x
pubmed: 22288732
Hanaguri J, Nagai N, Yokota H, Kushiyama A, Watanabe M, Yamagami S, Nagaoka T (2022) Fenofibrate Nano-Eyedrops ameliorate Retinal Blood Flow Dysregulation and Neurovascular Coupling in type 2 Diabetic mice. Pharmaceutics 14(2):384. https://doi.org/10.3390/pharmaceutics14020384
doi: 10.3390/pharmaceutics14020384
pubmed: 35214116
pmcid: 8876509
Formaz F, Riva CE, Geiser M (1997) Diffuse luminance flicker increases retinal vessel diameter in humans. Curr Eye Res 16(12):1252–1257. https://doi.org/10.1076/ceyr.16.12.1252.5021
doi: 10.1076/ceyr.16.12.1252.5021
pubmed: 9426960
Polak K, Schmetterer L, Riva CE (2002) Influence of flicker frequency on flicker-induced changes of retinal vessel diameter. Invest Ophthalmol Vis Sci 43(8):2721–2726
pubmed: 12147608
Yang S, Zhang J, Chen L (2020) The cells involved in the pathological process of diabetic retinopathy. Biomed Pharmacother 132:110818. https://doi.org/10.1016/j.biopha.2020.110818
doi: 10.1016/j.biopha.2020.110818
pubmed: 33053509
Mills SA, Jobling AI, Dixon MA, Bui BV, Vessey KA, Phipps JA, Greferath U, Venables G, Wong VHY, Wong CHY, He Z, Hui F, Young JC, Tonc J, Ivanova E, Sagdullaev BT, Fletcher EL (2021) Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy. Proc Natl Acad Sci U S A 118(51):e2112561118. https://doi.org/10.1073/pnas.2112561118
doi: 10.1073/pnas.2112561118
pubmed: 34903661
pmcid: 8713803
Ly A, Yee P, Vessey KA, Phipps JA, Jobling AI, Fletcher EL (2011) Early inner retinal astrocyte dysfunction during diabetes and development of hypoxia, retinal stress, and neuronal functional loss. Invest Ophthalmol Vis Sci 52(13):9316–9326. https://doi.org/10.1167/iovs.11-7879
doi: 10.1167/iovs.11-7879
pubmed: 22110070
Coughlin BA, Feenstra DJ, Mohr S (2017) Müller cells and diabetic retinopathy. Vis Res 139:93–100. https://doi.org/10.1016/j.visres.2017.03.013
doi: 10.1016/j.visres.2017.03.013
pubmed: 28866025
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(7494):55–60. https://doi.org/10.1038/nature13165
doi: 10.1038/nature13165
pubmed: 24670647
pmcid: 3976267
Fletcher EL, Dixon MA, Mills SA, Jobling AI (2023) Anomalies in neurovascular coupling during early diabetes: a review. Clin Exp Ophthalmol 51(1):81–91. https://doi.org/10.1111/ceo.14190
doi: 10.1111/ceo.14190
pubmed: 36349522
Alarcon-Martinez L, Villafranca-Baughman D, Quintero H, Kacerovsky JB, Dotigny F, Murai KK, Prat A, Drapeau P, Di Polo A (2020) Interpericyte tunnelling nanotubes regulate neurovascular coupling. Nature 585(7823):91–95. https://doi.org/10.1038/s41586-020-2589-x
doi: 10.1038/s41586-020-2589-x
pubmed: 32788726
Alarcon-Martinez L, Shiga Y, Villafranca-Baughman D, Belforte N, Quintero H (2022) Pericyte dysfunction and loss of interpericyte tunneling nanotubes promote neurovascular deficits in glaucoma. Proc Natl Acad Sci U S A 119(7):e2110329119. https://doi.org/10.1073/pnas.2110329119
doi: 10.1073/pnas.2110329119
pubmed: 35135877
pmcid: 8851476
Oku H, Kodama T, Sakagami K, Puro DG (2001) Diabetes-induced disruption of gap junction pathways within the retinal microvasculature. Invest Ophthalmol Vis Sci 42(8):1915–1920
pubmed: 11431461
Ivanova E, Kovacs-Oller T, Sagdullaev BT (2017) Vascular pericyte impairment and Connexin43 gap Junction Deficit Contribute to Vasomotor decline in Diabetic Retinopathy. J Neurosci 37(32):7580–7594. https://doi.org/10.1523/JNEUROSCI.0187-17.2017
doi: 10.1523/JNEUROSCI.0187-17.2017
pubmed: 28674171
pmcid: 5551058
Kovacs-Oller T, Ivanova E, Bianchimano P, Sagdullaev BT (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 Discov 6:39. https://doi.org/10.1038/s41421-020-0180-0
doi: 10.1038/s41421-020-0180-0
pubmed: 32566247
pmcid: 7296038
Sörensen BM, Houben AJ, Berendschot TT, Schouten JS, Kroon AA, van der Kallen CJ, Henry RM, Koster A, Sep SJ, Dagnelie PC, Schaper NC, Schram MT, Stehouwer CD (2016) Prediabetes and type 2 diabetes are Associated with generalized microvascular dysfunction: the Maastricht Study. Circulation 134(18):1339–1352. https://doi.org/10.1161/CIRCULATIONAHA.116.023446
doi: 10.1161/CIRCULATIONAHA.116.023446
pubmed: 27678264
Cai J, Boulton M (2002) The pathogenesis of diabetic retinopathy: old concepts and new questions. Eye 16(3):242–260. https://doi.org/10.1038/sj.eye.6700133
doi: 10.1038/sj.eye.6700133
pubmed: 12032713
Stefansson E, Landers MB 3rd, Wolbarsht ML (1983) Oxygenation and vasodilatation in relation to diabetic and other proliferative retinopathies. Ophthalmic Surg 14(3):209–226. https://doi.org/10.3928/1542-8877-19830301-01
doi: 10.3928/1542-8877-19830301-01
pubmed: 6190118
Pemp B, Weigert G, Karl K, Petzl U, Wolzt M, Schmetterer L, Garhofer G (2009) Correlation of flicker-induced and flow-mediated vasodilatation in patients with endothelial dysfunction and healthy volunteers. Diabetes Care 32(8):1536–1541. https://doi.org/10.2337/dc08-2130
doi: 10.2337/dc08-2130
pubmed: 19478197
pmcid: 2713642
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. Invest Ophthalmol Vis Sci 50(9):4029–4032. https://doi.org/10.1167/iovs.08-3260
doi: 10.1167/iovs.08-3260
pubmed: 19369238
Martins B, Amorim M, Reis F, Ambrósio AF, Fernandes R (2020) Extracellular vesicles and MicroRNA: putative role in diagnosis and treatment of Diabetic Retinopathy. Antioxidants 9(8):705. https://doi.org/10.3390/antiox9080705
doi: 10.3390/antiox9080705
pubmed: 32759750
pmcid: 7463887
Seshadri S, Ekart A, Gherghel D (2016) Ageing effect on flicker-induced diameter changes in retinal microvessels of healthy individuals. Acta Ophthalmol 94(1):e35–42. https://doi.org/10.1111/aos.12786
doi: 10.1111/aos.12786
pubmed: 26149453