Retinal blood flow. 1.Retinal circulation. 1. Retinal circulation Ø Supplies the inner retinal layers Ø Non fenestrated capillaries

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1 Glucose Retinal blood flow Pournaras Jean-Antoine C Vitreoretinal Surgery Unit Constantly regulated hemodynamics assuming delivery of and metabolic substrates, as well as intact blood-retinal barriers are necessary requirements for the maintenance of retinal structure and function. The neuronal cells maintain energy state through the formation of ATP, produced by means of two fundamental metabolic pathways, glycolysis and oxidative phosphorylation. 1.Retinal circulation Ø Derives from the central retinal artery Ø Is an end-arterial system without anastomose Ø Capillaries form an inter-connecting two layer pattern Ø 3rd layer of radial peri-papillary capillaries Glucose These energy generating reactions, consumming and metabolic substrates, are essential for neuronal function (Na+/ K+, Glutamate uptake) 1. Retinal circulation Ø Supplies the inner retinal layers Ø Non fenestrated capillaries Techniques for measuring the retinal blood flow Ø Quantitative determinations of BF in animals. Radioactively labeled microspheres. Radioactive krypton desaturation, Hydrogen clearance, Laser speckle phenomenon Targeted dye delivery, Leukocyte dynamics by fluography Invasive laser Doppler flowmetry 1

2 Techniques for measuring the retinal blood flow Non-invasive techniques used in clinical research Bidirectional laser Doppler velocimetry (BLDV) Techniques for measuring the retinal blood flow Non-invasive techniques used in clinical research Measurements of the diameter (D) of retinal vessels: BLDV is based on the Doppler effect. BLDV, allows the measurement of absolute blood velocity values. Fundus photographs Retinal Vessel Analyzer (RVA) continuous recording of D changes (dynamic measurements) Vmean = Vmax / 2 Ø Retinal circulation 2. Regulation of the retinal blood flow Low level of flow (4% of total ocular BF) In primates ml/min/100g tissue. Human total retinal BF ( µl/min) High O 2 extraction ( 40%) Autoregulation: the ability of the retinal vascular bed to keep blood flow constant despite moderate variations of the PP m Guyton et al., 1973 the ability of a tissue to adapt blood flow to metabolic needs Guyton A, Coleman T: 1967 Ø Choroidal circulation 85% of total ocular blood flow Low O 2 extraction (3-4%) 60% of O 2 and 75% of glucose of retinal needs Alm A, Bill A, Young FA. The effects of pilocarpine and neostigmine on the blood flow through the anterior uvea in monkeys. A study with radioactively labelled microspheres. Exp Eye Res 1973; 15: Alm A, Tornquist P, Stjernschantz J. Radioactively labelled microspheres in regional ocular blood flow determinations. Bibl Anat 1977; Bill A. Circulation in the Eye. In: Renkin EM, Michel CC, eds. Handbook of physiology. Baltimore: Waverly Press, 1984: Wang Y, Lu A, Gil-Flamer JH, Tan O, Izatt JA, Huang D. Measurement of total blood flow in the normal human retina using Doppler Fourier-domain optical coherence tomography. Br J Ophthalmol 2009; 93: Riva CE, Grunwald JE, Sinclair SH, Petrig BL. Blood velocity and volumetric flow rate in human retinal vessels. Invest Ophthalmol Vis Sci 1985; 26: Alm A, Bill A. The oxygen supply to the retina. II. Effects of high intraocular pressure and of increased arterial carbon dioxide tension on uveal and retinal blood flow in cats. A study with radioactively labelled microspheres including flow determinations in brain and some other tissues. Acta Physiol Scand 1972; 84: Achieved by the modifications of the resistant vessels tone i.e.arterioles, capillaries F= ΔPPm x πr 4 / 8nL F is correlated to the vessels diameter Determinants of retinal vessels Diameter Ø Systemic determinants Innervation Blood gases ie. PaO 2, PaCO 2 Circulating molecules Determinants of retinal vessels Diameter Ø Systemic determinants Innervation Blood gases ie. PaO 2, PaCO 2 Circulating molecules Ø Local determinants Substances affecting the tone of smooth muscle cells and pericytes released by - the vascular endothelium - Neuro-glial activity Ø Local determinants Substances affecting the tone of smooth muscle cells and pericytes released by - the vascular endothelium - Neuro-glial activity 2

3 Mechanisms of the retinal BF regulation 3. Autoregulation of the retinal blood flow Metabolic mechanism Blood flow constant during variations of PP m PPm: MOAP- IOP Ø Neuro-glial signalling: nno/ lactate / PGs Ø Retinal Relaxing Factor (ET receptors?) Autoregulation to a MABP up to 41% Robinson F et al., IOVS 1986 Myogenic mechanism Endothelial cells Relaxation: NO/ PGI 2 / ET B1 Contraction: ET 1 (ET A / ET B2 ) / TXH 2 Pournaras CJ, Rungger-Brandle E, Riva CE, Hardarson SH, Stefansson E. Regulation of retinal blood flow in health and disease. Prog Retin Eye Res 2008; 27: Autoregulation of the retinal blood flow Blood flow constant during during variations of PPm PPm: MOAP- IOP Blood flow response to visual stimulation Autoregulation of blood flow to an increase of IOP up to 60 mmhg Alm and Bill Acta Phsysiol Sca 1972, Exp eye Res 1973 Autoregulatory retinal vascular resistance responses to abrupt decreases and increases in PPm. Riva et al., IOVS 1986 Flicker-induced change of diameter of retinal vessel, measured by RVA. Nagel E, Vilser W. Flicker observation light induces diameter response in retinal arterioles: a clinical methodological study. Br J Ophthalmol 2004; 88: Blood flow response to Blood gases Hyperoxia Diastolic arterial velocity of a human retinal artery The retinal hemodynamic alterations affect: Ø the delivery of the retinal O 2 and metabolic substrates, Ø the integrity of the blood retinal barriers, Ø Blood flow changes induces ischemia tissue hypoxia and intracellular edema Ø Blood flow dysregulation leads to BRB barriers breakdown and extra-cellular edema Effect of hyperoxia on the D of retinal arteries in the four quadrants of the fundus 60% decrease of the RBF Riva CE, Grunwald JE, Sinclair SH. Laser Doppler velocimetry study of the effect of pure oxygen breathing on retinal blood flow. Invest Ophthalmol Vis Sci 1983; 24: Jean-Louis S, Lovasik JV, Kergoat H. Systemic hyperoxia and retinal vasomotor responses. Invest Ophthalmol Vis Sci 2005; 46:

4 Retinal BF decrease and dysregulation Ø Hypertensive retinopathy Endothelial function of the retinal vessels is impaired in early Hypertensive retinopathy Narrowed retinal arterioles are associated with long term risk of HTA. Structural alterations of the microvasculature/ impaired regulation may be linked to the development of hypertension. Wong T Y et al., BJO 2005 essential hypertension. Delles C, et al., Stroke 2004 Ø Diabetic retinopathy Altered myogenic and hyperoxic response of retinal arterioles Blum M et al., Ophthalmologe 2003 and 2006 Ø Decreased retinal BF occurs in PDR and RVO Grunwald et al. 1993, Avilla et al., 1998 Endothelial function of the retinal vasculature is impaired in early essential hypertension. Can be improved by AT 1 -receptor blocker Delles C, et al., Stroke 2004 Retinal Vein Occlusion: Mechanisms Exp. Retinal Ischemic Microangiopathy Decrease of the retinal blood flow Ø Arteriolar sclerosis Ø Rheologic factors Ø Thrombosis Ø Hemodynamic Increased circulating ET-1 levels in patients with RVO may be a marker of the occlusive event ET-1 plasma levels Normals pg/ml; p < 0.05 HTA pg/ ml; p <0.05 RVO pg/ml RVO isch pg/ml; p < 0.01 Iannaccone A. et al., Br J Ophthalmol 1998 Pournaras, C.J., Tsacopoulos, M., Strommer, K., Gilodi, N., Leuenberger, P. Ophthalmology 97, Donati, G., Pournaras, C.J., Pizzolato, G.P., Tsacopoulos, M., Invest. Ophthalmol. Vis. Sci. 38, weeks Decrease in arteriolar diameter 1 hour 22.8 ± 3.8% 2 hours 25.4 ± 3.4% leading to tissue hypoxia RVO: Circulation Modifications Decreased arteriolar flow The Vasodilatory Effect of Juxta-arteriolar Microinjection of Endothelin A Receptor Inhibitor in Healthy and Acute Branch Retinal Vein Occlusion Minipig Retinas. A.N. Stangos, I.K. Petropoulos, J-A.C. Pournaras, E.Mendrinos, and C.J. Pournaras. Invest Ophthalmol Vis Sci. 2010;51: NO decrease Myogenic vasoconstriction / ET 1 Donati et al., IOVS 1997 The Effect of Acute Experimental Retinal Vein Occlusion on Cat Retinal Vein Pressures. Attariwala R. et al., IOVS 1997 A significant increase in retinal arteriolar diameter was demonstrated after juxtaarteriolar BQ-123 microinjection in healthy and in acute BRVO minipig retinas. The results suggest a role for endothelin-1 in maintaining retinal basal arteriolar tone. 4

5 Retinal vein occlusions: The potential impact of a dysregulation of the retinal veins. S.A. Fraenkl, M. Mozaffarieh, J. Flammer EPMA Journal (2010) 1: Ø Blood retinal barrier breakdown Paracellular hyper-permeability Inflammatory mediators VEGF expression and BRB changes leukocytes related release of inflammatory mediators Atherosclerosis and Vascular dysregulation: Due to alterations to the arterial wall and its adventitia, Endothelin-1 is overexpressed in endothelial cells and by cells of the surroundings of the atherosclerotic arteries. As consequence, the vein constricts and in extreme situation a RVO results Tolentino, M.J. Pathologic Features of Vascular Endothelial Growth Factor-induced Retinopathy in the Nonhuman Primate, AJO 2002 Vaso-permeability factors and mac. Edema tissue hypoxia and VEGF VEGF expression and BRB changes Macular edema- Inciting molecules Ø Prostaglandins PGE1 PGE2 PGF2α Ø Leukotrienes LTB4 LTC4 LTD4 Ø Nitric oxide Ø PKCβ Ø Cytokines VEGF-A TNF-α IL-1β IGF-1 IL-6 SDF-1 ICAM-1 VEGF and IL-6 Increased in BRVO Correlated to macular edema Noma et al., Am J Ophthalmol 2005 Hypoxia and VEGF induce permeability through rearrangement of endothelial junctional proteins Fischer S et al., J. Cell. Physiol. 198: , 2004 VEGF expression and BRB changes Diabetic retinopathy The structural alterations of the retinal vessels in diabetes are attributed to: Ø vascular endothelium injuries Ø dysfunction of flow and/or the flow regulation Ø Abnormal regulation of the retinal blood flow has been demonstrated in patients with PDR Inhibition of VEGF signaling causes loss of endothelial fenestrations and regression of tumor vessels. Inai T. et al., American Journal of Pathology

6 Retinal arteriolar dys-regulation Vasodilatation Diabetic retinopathy Abnormal regulation of the RBF Poiseuille Law capillaries and veinules intra-luminal pressure increase The myogenic response of retinal arterioles in diabetic retinopathy Blum M et al., Ophthalmologe : Vasoconstriction of retinal arterioles with oxygen breathing in DR Blum M et al., Ophthalmologe : Starling Law Laplace Law Increase of exudation et reduction of re-absorption Extracellular Œdema Capillaries and veinular dilatation, increase of vessels length and tortuosity Group I 7.6% (±4.1) Group II 0.85% (±4.3) Group III +0.44% (±5.9) Group IV +3.2% (±5.9) Group I: no DR / Group II: mild/moderate DR, Group I - 6.2% (±4.0) Group II - 6.1% (±2.8) Group III - 6.6% (±4.1) Group IV +2.5% (±4,7) Group III: moderate/severe NPDR + laser Group IV: PDR with laser tr. PDR: recovery of flow regulation PRP and arteriolar vasoconstriction Oxygen and recovery of flow regulation PRP and blood flow regulation Decrease of the retinal blood flow under hyperoxia Normals 60% Riva et al., 1983 PDR 20 +/- 15% Grunwald 1986 PDR + laser 45 +/- 12% Grunwald 1986 E. Mendrinos, G. Mangioris, D.N. Papadopoulou, A. Dosso, C.J. Pournaras Retinal vessel analyzer measurements of the effect of PRP on the retinal arteriolar diameter in diabetic retinopathy. Retina Recovery of blood flow regulation following PRP Conclusions Conclusions The vascular tone of the resistant vessels (arterioles, capillaries) in the retina is modulated by the interaction of multiple mechanisms affecting the arteriolar smooth muscle and the vascular pericytes. The retinal blood flow is autoregulated by the interaction of myogenic and metabolic mechanisms through the release of vasoactive substances by the retinal tissue surrounding the arteriolar wall and/or the vascular endothelium. The interaction of metabolic pathways is implicated in the control of the vasomotion and autoregulation in the inner retina in order to maintain constant the retinal blood flow. Impairment of structure and function of the retinal neuronal tissue and endothelium leads to the retinal blood abnormal regulation observed during the evolution of ischemic microangiopathies. 6