Decrease In Retinal Blood Flow Research Articles

Alterations in Retinal Vascularity in Severe Psoriasis

ABSTRACT Purpose To evaluate the changes in retinal vascularity in patients with severe psoriasis. Materials and Methods Patients with severe psoriasis [psoriasis area-severity index (PASI) >10] who did not get any systemic treatment in the last year and do not have any ocular diseases were included. All patients underwent detailed ophthalmological examination, including optical coherence tomography (OCT) and OCT angiography (OCTA). Vessel densities (VD) of Superficial (SCP) and deep (DCP) capillary plexus, foveal avascular zone (FAZ) diameter, central retinal thickness (CRT) were analyzed and compared with age-sex matched healthy adults. Results Fifty-three patients (13 F, 40 M) and 56 controls (16 F, 40 M) were included in the study. VD of SCP (50.4%±3.9 vs. 51.4%±3.2) and DCP (52.6%±6.4 vs. 55.4%±5.7) were lower in psoriasis group compared to controls (p < .05). Presence of psoriatic arthritis was related with an increased CRT (p = .000), larger FAZ and decreased foveal VD in SCP (p = .01, p = .02, respectively). Conclusion Severe psoriasis causes a decrease in retinal blood flow and presence of psoriatic arthritis is related with decreased foveal VD.

Candesartan Normalizes Changes in Retinal Blood Flow and p22phox in the Diabetic Rat Retina.

Angiotensin II has been implicated in the progression of diabetic retinopathy, which is characterized by altered microvasculature, oxidative stress, and neuronal dysfunction. The signaling induced by angiotensin II can occur not only via receptor-mediated calcium release that causes vascular constriction, but also through a pathway whereby angiotensin II activates NADPH oxidase to elicit the formation of reactive oxygen species (ROS). In the current study, we administered the angiotensin II receptor antagonist candesartan (or vehicle, in untreated animals) in a rat model of type 1 diabetes in which hyperglycemia was induced by injection of streptozotocin (STZ). Eight weeks after the STZ injection, untreated diabetic rats were found to have a significant increase in tissue levels of angiotensin converting enzyme (ACE; p < 0.05) compared to non-diabetic controls, a 33% decrease in retinal blood flow rate (p < 0.001), and a dramatic increase in p22phox (a subunit of the NADPH oxidase). The decrease in retinal blood flow, and the increases in retinal ACE and p22phox in the diabetic rats, were all significantly attenuated (p < 0.05) by the administration of candesartan in drinking water within one week. Neither STZ nor candesartan induced any changes in tissue levels of superoxide dismutase (SOD-1), 4-hydroxynonenal (4-HNE), or nitrotyrosine. We conclude that one additional benefit of candesartan (and other angiotensin II antagonists) may be to normalize retinal blood flow, which may have clinical benefits in diabetic retinopathy.

Relationship between breathing gas mixtures and retinal vessel regulation

PurposeIt is known that components of oxygen transport pathway communicate with vascular endothelium. However, oxygen‐induced vessel constriction results in a decrease in retinal blood flow. Because the delivery and removal of metabolites and gases is proportional to blood flow, a decrease in blood flow could have deleterious effects. Due to the systemic nature of the endothelium, this should be taken into account wherever breathing gas mixture is changed (anesthesia). This work aims to clarify how the constriction of the retinal vessels is modulated by breathing gas mixtures using dynamic vessel analysis (DVA).MethodsThe baseline diameters of 15 volunteers (9 m, 26.3 ± 3.3 y) were measured using DVA (Imedos Systems GmbH). We investigated four primary vessel segments (superior as well as inferior temporal artery (STa/ITa) and vein (STv/ITv). For each volunteer, the DVA was performed 5 times (each: duration 15 min [1 min baseline, 8 min gas mixture, 6 min recovery], rest period: 10 min) in a randomized order using different gas mixtures (21%, 30%, 40%, 50%, 60% O2) provided by a ventilator (Bellavista 1000, imtmedical AG). For statistical analysis, the t‐test and the Wilcoxon test for paired samples (Bonferroni corrected) were used.ResultsFor all vessel segments, a stronger constriction could be observed with an increase in the oxygen concentration. The maximum constriction was always measured at the end of the 8 min period. Here, when comparing the constriction values of the 21% O2 concentration, already the 30% O2 concentration showed significant changes (30%/40%/50%/60% STa: p = 0.002/0.001/0.000/0.000, ITa: p = 0.001/0.001/0.001/0.000, STv: p = 0.000/0.000/0.000/0.000, ITv: p = 0.001/0.000/0.000/0.000).ConclusionsThe presented work revealed that even a small change in breathing gas mixture causes a significant change in vessel constriction. These effect is not only to be expected at the retina, but also in the brain as an example. This should be taken into account, amongst others, for longer anesthesia.

Blood flow distribution and the endothelial surface layer in the diabetic retina.

Diabetic retinopathy is known as a microvascular complication of hyperglycemia, with a breakdown of the blood-retinal barrier, loss of pericytes, formation of microhemorrhages, early decreases in perfusion and areas of ischemia, with the latter speculated to induce the eventual proliferative, angiogenic phase of the disease. Our animal models of diabetic retinopathy demonstrate similar decreases in retinal blood flow as seen in the early stages of diabetes in humans. Our studies also show an alteration in the retinal distribution of red blood cells, with the deep capillary layer receiving a reduced fraction, and with flow being diverted more towards the superficial vascular layer. Normal red blood cell distribution is dependent on the presence of the endothelial surface layer, specifically the glycocalyx, which has been reported to be partially lost in the diabetic retina of both humans and animals. This review addresses these two phenomena in diabetes: altered perfusion patterns and loss of the glycocalyx, with a possible connection between the two.

Changes in Ganglion Cell–Inner Plexiform Layer Thickness and Retinal Microvasculature in Hypertension: An Optical Coherence Tomography Angiography Study

To investigate retinal blood flow in patients with hypertension using optical coherence tomography angiography (OCTA) and the relationship between blood flow metrics and ganglion cell-inner plexiform layer (GC-IPL) thickness. Retrospective, cross-sectional study. A total of 201 eyes from 117 healthy subjects and 84 hypertensive patients without any ocular abnormalities were included. Hypertensive patients were divided into the 2 groups according to disease periods (<5 years: Hypertension Group 1; ≥5 years: Hypertension Group 2). Macular 3× 3-mm angiography was acquired using the Zeiss Cirrus 5000 OCT instrument. Vessel density (VD), perfusion density (PD), and foveal avascular zone metrics of the superficial capillary plexus were automatically calculated, and the thicknesses of the central fovea, GC-IPL, and peripapillary retinal nerve fiber layer (RNFL) were measured. All measurements were compared among the 3 groups, and retinal blood flow metrics were correlated with the thickness of each retinal layer. Logistic regression analyses were performed to determine the factors associated with prolonged hypertension. The average GC-IPL (P < .001) and peripapillary RNFL (P= .048) thicknesses in Hypertension Group 2 were significantly thinner compared to the control group. The 3mm total area of the VD and PD was also decreased compared to the control group and Hypertension Group 1 (all P < .05), and was significantly correlated with the GC-IPL (VD: r= 0.450, P=.001; PD: r= 0.467, P < .001) and peripapillary RNFL (VD: r= 0.314, P= .027; PD: r= 0.328, P=.023) thicknesses in Hypertension Group 2. Using multivariate logistic analyses, only the average GC-IPL thickness was a significant factor for prolonged hypertension (odds ratio= 0.911, P= .002). In patients with hypertension lasting more than 5 years, inner retinal layer thinning, particularly GC-IPL thinning, was observed, which was significantly correlated with a decrease in retinal blood flow. Therefore, physicians should consider the effects of hypertension on the GC-IPL.

Role of glial cells in regulating retinal blood flow during flicker‐induced hyperemia and systemic hyperoxia‐induced hyporemia in cats

SummaryBackgroundTo investigate the role of glial cells in the regulation of retinal circulation in response to flicker stimulation, which is related to neurovascular coupling, and systemic hyperoxia in the retina.MethodsUsing laser Doppler velocimetry, we measured the retinal blood flow (RBF) in first‐order retinal arterioles in anesthetized cats. After intravitreal injection of l‐2‐aminoadipic acid (LAA) as gliotoxic compound, we examined the changes in RBF in response to flicker stimulation of 16 Hz for 3 min and systemic hyperoxia induced by the inhalation of 100% oxygen for 10 min.ResultsThe RBF increased gradually and reached a maximal level after 2–3 min of flicker stimuli in the PBS group. In the LAA‐treated eyes, the increases in RBF during the flicker stimulation were significantly attenuated by one third of those in the control eyes. During hyperoxia, the decreases in RBF in response to hyperoxia were significantly attenuated in the LAA‐treated eyes compared with the control.ConclusionsThe current results suggest that the retinal glial cells play an important role in the regulation of retinal blood flow during Flicker‐Induced Hyperemia and Systemic Hyperoxia‐Induced Hyporemia.

Optical coherence tomography angiography in glaucoma diagnosis

According to literature data, vascular dysfunction may well contribute to the development of glaucomatous optic neuropathy, which makes it reasonable to search for new imaging techniques capable of early diagnosis and monitoring of glaucoma through assessment of retinal, optic nerve head (ONH), and choroidal perfusion. Optical coherence tomography angiography (OCTA), a recently introduced method based on the split-spectrum amplitude-decorrelation angiography (SSADA) algorithm, enables evaluation of both retinal and choroidal blood flow in peripapillary and macular areas. The first studies involving OCTA have revealed a decrease in retinal blood flow in glaucoma. It has also been shown that visual field indices correlate better with the peripapillary flow index than with morphometric parameters of the optic nerve head (ONH) and peripapillary retina. OCT angiography has great potential for ONH blood flow assessment during physiological tests, which is an important step towards understanding pathogenesis of glaucoma.

Measurement of retinal blood flow in the rat by combining Doppler Fourier-domain optical coherence tomography with fundus imaging.

A wide variety of ocular diseases are associated with abnormalities in ocular circulation. As such, there is considerable interest in techniques for quantifying retinal blood flow, among which Doppler optical coherence tomography (OCT) may be the most promising. We present an approach to measure retinal blood flow in the rat using a new optical system that combines the measurement of blood flow velocities via Doppler Fourier-domain optical coherence tomography and the measurement of vessel diameters using a fundus camera-based technique. Relying on fundus images for extraction of retinal vessel diameters instead of OCT images improves the reliability of the technique. The system was operated with an 841-nm superluminescent diode and a charge-coupled device camera that could be operated at a line rate of 20 kHz. We show that the system is capable of quantifying the response of 100% oxygen breathing on the retinal blood flow. In six rats, we observed a decrease in retinal vessel diameters of 13.2% and a decrease in retinal blood velocity of 42.6%, leading to a decrease in retinal blood flow of 56.7%. Furthermore, in four rats, the response of retinal blood flow during stimulation with diffuse flicker light was assessed. Retinal vessel diameter and blood velocity increased by 3.4% and 28.1%, respectively, leading to a relative increase in blood flow of 36.2%. The presented technique shows much promise to quantify early changes in retinal blood flow during provocation with various stimuli in rodent models of ocular diseases in rats.

Autoregulation of Retinal Blood Flow in Response to Decreased Ocular Perfusion Pressure in Cats: Comparison of the Effects of Increased Intraocular Pressure and Systemic Hypotension

To investigate the regulatory mechanisms responsible for autoregulation of retinal blood flow (RBF) during periods of decreased ocular perfusion pressure (OPP). The effects of acute reductions in OPP on RBF were assessed using laser Doppler velocimetry in cats. The OPP decreased from 90 to 40 mm Hg by increasing the IOP (elevated IOP) or by decreasing the systemic blood pressure via exsanguination (systemic hypotension). The contributions of nitric oxide (NO), adenosine, and/or N-methyl-D-aspartic acid (NMDA) in regulation of the retinal arteriolar hemodynamics during decreased OPP was determined at 120 minutes after intravitreal injection of various inhibitors or PBS. Following PBS injection, the flow velocity decreased in proportion to the decrease in OPP; however, the retinal arteriolar diameter gradually increased. Consequently, the RBF was maintained near baseline levels when the OPP exceeded 70 mm Hg but decreased significantly (P < 0.01) when the OPP fell to less than or equal to 60 mm Hg due to elevated IOP or systemic hypotension. Adenosine receptor blocker 8-(p-sulfophenyl)theophylline, significantly (P < 0.01) enhanced decreases in RBF induced by elevated IOP and systemic hypotension at OPP from 80 to 40 mm Hg, whereas NO synthase inhibitor N(G)-nitro-L-arginine-methyl ester and NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid only significantly (P < 0.01) enhanced reductions in RBF induced by elevated IOP. These results indicate that adenosine contributes to autoregulation of RBF during systemic hypotension, whereas adenosine, NO, and NMDA receptors autoregulate the RBF after elevated IOP. Different vasoregulatory factors might contribute to autoregulation of RBF after decreases in OPP induced by elevated IOP and systemic hypotension.

Effect of systemic hyperoxia on retinal oxygen saturation

AbstractPurpose Several groups have reported that 100% oxygen breathing caused an increase in retinal venous oxygen saturation. In the present study we set out to study the effects of 100% oxygen breathing on retinal blood flow and retinal oxygen saturation to gain more insight into the regulation of retinal oxygenation.Methods 30 healthy volunteers were included into the present study. The effect of 100% oxygen breathing on retinal blood velocities was performed using laser Doppler velocimetry (LDV). Retinal vessel diameters were measured with the Dynamic Vessel Analyzer (DVA, Imedos, Germany). Retinal oxygen saturation was evaluated in retinal arteries and retinal veins using spectroscopy also employing the DVA. The effect of 100% oxygen breathing on systemic oxygen tension was evaluated based on arterialized blood samples drawn from the earlobe.Results Breathing 100% oxygen caused systemic hyperoxia as evidenced from a pronounced increase in systemic oxygen tension (p &lt; 0.001). Oxygen saturation increased in both retinal arteries and retinal veins (p &lt; 0.05 each) but the effect in veins was more pronounced. As expected we observed a decrease in retinal vessel diameters, retinal blood velocities as well as in retinal blood flow (p &lt; 0.001 each).Conclusion The results are compatible with the idea that increased venous oxygen saturation during 100% oxygen breathing is due to a pronounced decrease in retinal blood flow. In addition, our data indicate unchanged retinal oxygen extraction during hyperoxia.

Measurement of retinal blood flow rate in diabetic rats: disparity between techniques due to shunting of capillary flow

The objective of this study was to clarify whether retinal blood flow (RBF) rates are altered in rats during streptozotocin (STZ)‐induced diabetes. Reports of this possibility in the literature are mixed, possibly due to the different techniques used to measure RBF. STZ (or vehicle alone, in controls) was injected into the rats (30 mg/kg for 3 days) to induce a model of type I diabetes. Eight weeks later, RBF rates were measured in the anesthetized rats using intravital microscopy and a fluorescent tracer (FITC‐dextran) in a mean circulation (transit) time index of flow. In separate rats, RBF was measured using a microsphere infusion technique. The induction of diabetes resulted in a 30–35% decrease in RBF (***p&lt;0.001) in the STZ rats as determined by the microsphere measurement. However, in a striking contrast to these results, the mean transit times of injected FITC‐dextran were ~3× faster in the STZ rats compared with the controls (**p&lt;0.01). We hypothesize that this discrepancy is due to shunting of RBF away from the deep retinal capillary layers in the STZ rats, with the altered flow pattern allowing the rapid transit of tracer from the arterioles into the venules. Funded by NIH EY017599 (NRH).

Effects of increased white blood cell count on endothelin-induced vasoconstriction in healthy subjects

It is known that administration of granulocyte-colony stimulating factor is followed by an increase of white blood cell count. There is evidence from other vascular beds that an increase in white blood cell count impairs blood flow regulation especially in the microcirculation. Whether this also holds true for the ocular circulation is unknown. In the following study we investigated whether an increase in white blood cell count alters the endothelin-1 induced vasoconstriction in humans. Neither granulocyte-colony stimulating factor nor endothelin-1 had any consistent effect on blood pressure, pulse rate or intraocular pressure. Administration of granulocyte-colony stimulating factor induced a pronounced increase in retinal white blood cell density (p < 0.01). Administration of endothelin-1 decreased choroidal (p < 0.01) and retinal blood flow (p < 0.01). The change in choroidal blood flow in response to endothelin-1 was not altered by pre-treatment with granulocyte-colony stimulating factor. By contrast, the decrease in retinal blood flow was more pronounced during an increase in white blood cell count (p = 0.02) when compared to placebo. Our data indicates that during pronounced vasoconstriction, as induced by administration of endothelin-1, vascular regulation can be altered by the number of circulating white blood cells. Whether this effect is caused by an interaction of red and white blood cells in the microcirculation or a yet unknown mechanism needs further investigation.

Effects of increased neutrophile count on ET1 – induced changes in erythrocyte and leukocyte movements

AbstractPurpose It is known that granulocyte‐colony stimulating factor (G‐CSF) increases white blood cell (WBC) count. There is evidence from other vascular beds that an increase in WBC count impairs blood flow regulation in the microcirculation. Whether this also holds true for the ocular circulation is yet unknown. In the following trial we investigated whether an increase in WBC count alters the endothelin‐1 (ET‐1) induced vasoconstriction.Methods 24 healthy male subjects entered this randomized, placebo‐controlled, double masked, two‐way cross over study. 300µg G‐CSF or placebo were applied intravenously to increase WBC count on two study days. Thereafter, ET‐1 (5ng/kg/min) was infused for 30 minutes. Ocular hemodynamic variables were measured before and after G‐CSF treatment and during the last 10 minutes of ET‐1 infusion. Measurements of retinal WBC flux were performed with the blue‐field entoptic technique, blood flow (BF) velocity using a laser Doppler velocimeter and retinal vessel diameter using a Retinal Vessel Analyzer.Results Neither G‐CSF nor ET‐1 had any consistent effect on blood pressure, pulse rate or IOP. G‐CSF induced an increase in retinal WBC density (p&lt;.01). As expected ET‐1 lowered choroidal BF (p&lt;.01), retinal BF (p&lt;.01)and WBC velocity (p=.01). Changes in choroidal BF and WBC velocity in response to ET‐1 were not altered by pre‐treatment with G‐CSF. Contrary, the decrease in retinal BF was more pronounced during leukocytosis (p=.02) as compared to placebo.Conclusion During vasoconstriction, induced by ET‐1, vascular regulation can be altered by the number of circulating leukocytes. Whether this is caused by an interaction of red and white blood cells or by another mechanism is yet unknown.

Increase in retinal hypoxia-inducible factor-2α, but not hypoxia, early in the progression of diabetes in the rat

Hypoxia and the associated hypoxia-inducible factors (HIFs) may be influential in the progression of diabetic retinopathy. However, little is known of the extent of hypoxia and the levels of HIFs early in the progression of the disease. In the current study, we injected the oxygen-dependent probe pimonidazole (Hypoxyprobe™-1) into diabetic rats, and also performed immunohistochemistry to determine the retinal levels of HIF-1α and HIF-2α. The rats were made diabetic using a single injection of streptozotocin (STZ; 60 mg/kg), with vehicle-injected rats used as non-diabetic controls. The measurements of hypoxia and HIF levels were obtained three weeks following STZ injection, at which time we have previously found significant decreases in retinal blood flow in the same model. In the current experiments, no increases in either HIF-1α or hypoxia were observed in the diabetic rats (compared with controls), and there was even a tendency for hypoxia levels to be decreased (tissue more highly oxygenated). However, we did observe an increase in HIF-2α in the retinas of the diabetic rats. Therefore, we conclude that early diabetes-induced increases in HIF-2α occur independently of hypoxia.

Inhibition of 20-HETE attenuates diabetes-induced decreases in retinal hemodynamics

The mechanisms of early diabetes-induced decreases in retinal blood flow have yet to be fully determined. The aim of this study was to explore the hypothesis that 20-hydroxyeicosatetraenoic acid (20-HETE) plays a role in the early decrease of retinal hemodynamics in diabetic mice. 20-HETE has been implicated previously in the diabetes-enhanced vasoconstriction of mesenteric and renal vessels; however, its role in the diabetic retinal microcirculation has not been investigated. Diabetes was induced by multiple low-dose injections of streptozotocin (STZ; 50 mg/kg for 5 consecutive days), then ∼2 weeks later the mice were administered daily intraperitoneal injections with or without the 20-HETE inhibitor HET0016 (2.5 mg/kg/day) for the following 2 weeks. Non-diabetic age-matched mice were included as controls. Intravital microscopy was used to obtain measurements of retinal vascular diameters and red blood cell (RBC) velocities for the feed arterioles and draining venules extending out of and into the optic disk. From these values, wall shear rates and blood flow rates were calculated. Diabetes induced approximately 30–40% decreases in RBC velocity, wall shear rate, and blood flow rate. These decreases were attenuated to 5–10% in the mice given HET0016. In summary, the 20-HETE inhibitor HET0016 is able to attenuate the retinal hemodynamic changes induced by diabetes.

Effect of Tempol on Diabetes-Induced Decreases in Retinal Blood Flow in the Mouse

Purpose: The purpose was to investigate the effect of the superoxide dismutase mimetic tempol on decreases in retinal blood flow that are found in diabetic mice.Materials and Methods: Streptozotocin (STZ) was injected into male C57BL/6 mice to induce hyperglycemia. One week following the STZ injection, subsets of the mice were given drinking water with or without 1 mM tempol for an additional three weeks. At the end of the four-week protocol, microvascular parameters were quantified via intravital microscopy, and included measurements of retinal diameters, red blood cell (RBC) velocities, blood flow rates, and wall shear rates.Results: Diabetes induced ~40–45% decreases in retinal blood flow rate (p < 0.001) four weeks following injection of STZ. The decrease in blood flow rate occurred with decreases in microvascular diameters (D) and RBC velocities (V). The average percentage decrease in velocity was greater than the percentage decrease in diameter and, therefore, wall shear rates (= 8 V/D) were ~25% lower in the diabetics than in the non-diabetics (p < 0.05). A three-week administration of tempol in the STZ mice allowed significantly higher blood flow rates than in the untreated STZ mice, with RBC velocities improved by the antioxidant (p < 0.05 on the venular side). However, tempol provided only moderate (and not statistically significant) improvements in wall shear rates.Conclusions: The antioxidant tempol provides partial improvements in retinal microvascular hemodynamics early in the progression of STZ-induced diabetes in mice.

Attenuation of streptozotocin-induced microvascular changes in the mouse retina with the endothelin receptor A antagonist atrasentan

Hyperglycemia mediates endothelial cell dysfunction through a number of potential mechanisms that could result in the decrease of retinal blood flow early in diabetes. The aim of this study was to explore the role of endothelin receptor A (ET A) in the early decrease of retinal blood flow in diabetic mice. Diabetes was induced by streptozotocin, then ∼1 wk later the mice were administered drinking water with or without the ET A receptor antagonist atrasentan (7.5 mg/kg/day) for the following 3 weeks. Non-diabetic age-matched mice with or without atrasentan were included as controls. For each mouse, measurements of retinal vascular diameters and red blood cell (RBC) velocities were obtained via intravital microscopy for the 5–7 feed arterioles (and draining venules) extending out of (and into) the optic disk, and from these values, flow rates and wall shear rates were calculated. Additionally, the number of retinal capillaries was counted by fluorescent immunostaining of platelet-endothelial cell adhesion molecule-1 (PECAM-1). Diabetes induced statistically significant decreases in RBC velocity, flow rate, and wall shear rate, with these alterations partially inhibited by atrasentan. No changes were observed in PECAM-1 expression among groups. The changes induced by diabetes, and the attenuation provided by atrasentan, were greater in the smaller retinal arterioles. In summary, ET A appears to play a role in the early decreases in retinal blood flow in a mouse model of diabetes.

Hypoxia and the expression of HIF-1α and HIF-2α in the retina of streptozotocin-injected mice and rats

Decreases in retinal blood flow in diabetics could render the retina hypoxic. In mouse and rat models of diabetes, a decrease in retinal blood flow occurs early, within 3–4 weeks of the induction of hyperglycemia, although information is scarce on whether this early decrease in flow induces hypoxia. The purpose of the current study was to determine whether hypoxia-inducible factor (HIF) levels increase following 4 and/or 12 weeks of hyperglycemia in streptozotocin (STZ)-injected mouse (C57BL/6) and rat (Wistar) retinas. Additionally, retinal tissue hypoxia was measured with pimonidazole following 12 weeks of hyperglycemia. These aims were accomplished via immunostaining of cross-sections from enucleated eyes. In mice, staining for HIF-1α and HIF-2α showed a contrasting pattern, with HIF-1α higher in the inner retina than outer, but HIF-2α higher in the outer retina than inner. However, in rats, staining for both HIF-1α and HIF-2α was more intense in the inner retina. The HIF-1α staining intensities and patterns were similar between diabetic animals and their non-diabetic counterparts following 4 and 12 weeks of hyperglycemia. The same was true for HIF-2α except for a trend toward an increase following 12 weeks of hyperglycemia in mice. Pimonidazole staining showed significant decreases throughout all layers of the central retina and most layers of the peripheral retina of rats (but not mice), following 12 weeks of hyperglycemia. In summary, despite early decreases in flow in rats and mice, retinal HIF-1α and HIF-2α were not found to be increased, and the extent of hypoxia may even decrease after 12 weeks of hyperglycemia in rats.

Attenuation of diabetes-induced retinal vasoconstriction by a thromboxane receptor antagonist

Retinal blood flow has been reported to decrease early in human diabetes as well as in diabetic animal models. The purpose of the present study is to investigate the role of thromboxane receptor binding in the decrease of flow. C57BL/6 mice were injected with streptozotocin (STZ) at 11–12 weeks of age and remained hyperglycemic for 4 weeks. The mice were treated with a selective thromboxane receptor antagonist, GR32191B (vapiprost), in drinking water for the final three weeks at a dose of 1 mg/kg/day. In separate experiments, vapiprost was administered only once, as an acute injection 25 min prior to the experimental measurements. The measurements included retinal arteriolar and venular diameters and red blood cell (RBC) velocities, from which retinal blood flow was calculated. STZ induced decreases in vascular diameters and RBC velocities, resulting in an approximate 30% decrease in overall retinal blood flow. However, these decreases were not seen in mice given the three-week administration of vapiprost. Acute administration to diabetic mice of 1 mg/kg vapiprost, but not 0.1 mg/kg, induced arteriolar vasodilation, with the dilation more substantial in smaller feed arterioles. In summary, STZ-induced decreases in retinal blood flow can be attenuated by the thromboxane receptor antagonist vapiprost.

Effects of antioxidants on ocular blood flow in the LPS‐induced inflammation model in humans

Abstract Purpose We set out to investigate whether the AREDS medication is capable of normalizing retinal blood flow reactivity to systemic hyperoxia in a human lipopolysaccharide (LPS) model. Methods The present study was a randomized double masked placebo‐controlled parallel group study in 21 healthy volunteers. The infusion of LPS was used as a standardized experimental model of systemic inflammation associated with enhanced oxidative stress and widespread endothelial dysfunction in humans. Ocular hemodynamic measurements were performed before endotoxemia and 4 hours after the subjects had received an LPS bolus. At each of these time points the retinal vascular reactivity to hyperoxia was studied. After the first trial day the subjects had to take either the AREDS medication (n=14) or a placebo (n=7) for 14 days. Thereafter a second trial day was performed on which the time schedule exactly followed the first day as described above. Results As expected LPS induced retinal vasodilatation (p &lt; 0.01) together with an increase in retinal leukocyte density, which occurred because to systemic leukocytosis. The oxygen induced decrease in retinal blood flow was reduced after infusion of LPS (p &lt; 0.01). This effect was partially restored after intake of the AREDS medication, but not after intake of placebo (p = 0.04) between groups. Conclusion Our findings support previous data showing that LPS induces impaired endothelial function. This effect was significantly reduced by the AREDS medication. Our model may be used to study the effects of various antioxidants and the components of the AREDS medication on oxidative stress‐induced vascular dysregulation in the human retina.