Effect of insulin treatment on pulsatility ratio and resistance index of the retinal artery in patients with type 2 diabetes.

This study aimed to evaluate whether long-term insulin treatment is associated with abnormalities in retinal circulation in type 2 diabetic patients. We evaluated 19 eyes of nondiabetic individuals and 68 eyes of type 2 diabetic patients. The eyes of diabetic patients were classified into two groups according to the presence or absence of long-term insulin therapy. We used a Doppler optical coherence tomography flowmeter to measure diameter, velocity, and blood flow in the major temporal retinal artery. The pulsatility ratio (PR) and resistance index (RI), indices of vascular rigidity, were calculated from the blood velocity profile. PR and RI were significantly elevated in type 2 diabetic patients compared with nondiabetic subjects (P < 0.05). In type 2 diabetes patients, PR and RI were significantly higher in patients receiving long-term insulin treatment than in those without (P < 0.01). There was a significant difference in velocity (P < 0.05), but not diameter and blood flow, between nondiabetic subjects and type 2 diabetes patients. No significant difference in diameter, velocity, or blood flow was observed between the groups with and without long-term insulin treatment. Long-term insulin treatment can affect PR and RI, which might be associated with vascular rigidity of the retinal artery in patients with type 2 diabetes.

Differential Effects of Intra- and Extravascular ATP on the Diameter of Porcine Vessels at Different Branching Levels Ex Vivo.

Purpose: Adenosine triphosphate (ATP) is involved in the diameter regulation of retinal vessels. The compound has been shown to induce both constriction and dilatation, but the detailed mechanisms underlying these effects and the site of action of the compound are not known in detail. Therefore, the purpose of the present study was to investigate whether the vasoactive effects of ATP on retinal vessels depend on intra- and extravascular application, and to study whether the effects differ at different vascular branching levels. Methods: Diameter changes in arterioles, pre-capillary arterioles, and capillaries were studied in perfused porcine hemiretinas (n = 48) ex vivo after intra- and extravascular application of the nondegradable ATP analogue ATP-γ-S or ATP in the presence or not of antagonists to the CD73/ecto-5'-nucleotidase (AOPCP), the P2-purinergic receptor (PPADS), the A3-adenosine receptor (MRS1523), and the synthesis of cyclooxygenase products (ibuprofen). Results: Intravascular ATP-induced constriction and extravascular ATP-induced dilatation of retinal arterioles, pre-capillary arterioles and capillaries, and dilatation was inhibited by ibuprofen. Both constriction and dilatation of arterioles were inhibited by antagonizing ATP degradation. Furthermore, constriction at all three branching levels was antagonized by blocking the A3 purinoceptor, whereas constriction in arterioles and pre-capillary arterioles was antagonized by blocking the P2 purinoceptor. Conclusions: ATP affects the diameter of retinal arterioles, pre-capillary arterioles, and capillaries through different pathways, and the effects depend on whether the compound is administered intravascularly or extravascularly. This may form the basis for selective interventions on retinal vascular disease with differential involvement of vessels at different branching levels.

Floralozone Ameliorated Atherosclerosis in Experimental Atherosclerotic Rats Involved with Sphingosine 1-Phosphate 1 Enhancement.

Atherosclerosis (AS) is a chronical pathological process of the arterial narrows due to the AS plaque formation. The aim of this study was to explore the therapeutic effect and the underlying mechanism of Floralozone on experimental atherosclerotic model rats. Experimental atherosclerotic model rats were induced by the right carotid artery balloon injury and intraperitoneal injection of vitamin D3 in rats after 4 weeks high-fat diet. The results exhibited that Floralozone could ameliorate vascular injury and vasorelaxation of descending aortas and increase the superoxide dismutase activity and the expression of sphingosine 1-phosphate (S1P) 1 and reduce the intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, interleukin (IL)-1, IL-6 level, and the malondialdehyde activity in experimental atherosclerotic rats. However, Fingolimod, an S1P1 inhibitor, could reverse these Floralozone effects in experimental atherosclerotic rats. Our results indicated that Floralozone could inhibit the atherosclerotic plaque formation and improves arterial stenosis and reduces endothelial dysfunction in experimental atherosclerotic rats, which might be involved with S1P1 enhancement.

Acute changes in the retina and central retinal artery with methamphetamine.

Methamphetamine (METH), an addictive stimulant of neurotransmitters, is associated with cardiovascular and neurological diseases. METH-induced ophthalmic complications are also present but have been insufficiently investigated. The purpose of this study is to investigate the retinal effects of METH. C57BL/6 mice were administrated progressively increasing doses of METH (0-6 mg/kg) by repetitive intraperitoneal injections for 5 days (4 times per day). Retinal degeneration was examined by morphological changes and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) assay. Norepinephrine levels were measured by ELISA, protein expression levels were determined by immunoblot and immunostaining, and gelatinase activity was examined by zymography. The thickness of the retina and the number of nuclei in the inner and outer nuclear layers were decreased by METH. Retinal cell death and astrocyte activation by METH treatment were confirmed by TUNEL assay and glial fibrillary acidic protein expression, respectively. Increased tumor necrosis factor-α protein in the retina and elevated norepinephrine levels in plasma were found in METH-treated mice. Platelet endothelial cell adhesion molecule-1 (PECAM-1) protein expression level was decreased in the retina and central retinal artery (CRA) by METH treatment, along with the endothelial proteoglycans glypican-1 and syndecan-1. Moreover, a regulator of the extracellular matrix, matrix metalloproteinase-14 (MMP-14) in the retina, and MMP-2 and MMP-9 in plasma, were increased by METH treatment. In conclusion, METH administration is involved in retinal degeneration with a vascular loss of PECAM-1 and the glycocalyx in the CRA and retina, and an increase of MMPs.

Newly Identified Peptide, Peptide Lv, Promotes Pathological Angiogenesis.

Background We recently discovered a small endogenous peptide, peptide Lv, with the ability to activate vascular endothelial growth factor receptor 2 and its downstream signaling. As vascular endothelial growth factor through vascular endothelial growth factor receptor 2 contributes to normal development, vasodilation, angiogenesis, and pathogenesis of various diseases, we investigated the role of peptide Lv in vasodilation and developmental and pathological angiogenesis in this study. Methods and Results The endothelial cell proliferation, migration, and 3-dimensional sprouting assays were used to test the abilities of peptide Lv in angiogenesis in vitro. The chick chorioallantoic membranes and early postnatal mice were used to examine its impact on developmental angiogenesis. The oxygen-induced retinopathy and laser-induced choroidal neovascularization mouse models were used for in vivo pathological angiogenesis. The isolated porcine retinal and coronary arterioles were used for vasodilation assays. Peptide Lv elicited angiogenesis in vitro and in vivo. Peptide Lv and vascular endothelial growth factor acted synergistically in promoting endothelial cell proliferation. Peptide Lv-elicited vasodilation was not completely dependent on nitric oxide, indicating that peptide Lv had vascular endothelial growth factor receptor 2/nitric oxide-independent targets. An antibody against peptide Lv, anti-Lv, dampened vascular endothelial growth factor-elicited endothelial proliferation and laser-induced vascular leakage and choroidal neovascularization. While the pathological angiogenesis in mouse eyes with oxygen-induced retinopathy was enhanced by exogenous peptide Lv, anti-Lv dampened this process. Furthermore, deletion of peptide Lv in mice significantly decreased pathological neovascularization compared with their wild-type littermates. Conclusions These results demonstrate that peptide Lv plays a significant role in pathological angiogenesis but may be less critical during development. Peptide Lv is involved in pathological angiogenesis through vascular endothelial growth factor receptor 2-dependent and -independent pathways. As anti-Lv dampened the pathological angiogenesis in the eye, anti-Lv may have a therapeutic potential to treat pathological angiogenesis.

Carbonic Anhydrase Inhibitors of Different Structures Dilate Pre-Contracted Porcine Retinal Arteries.

Carbonic anhydrase inhibitors (CAIs), such as dorzolamide (DZA), are used as anti-glaucoma drugs to lower intraocular pressure, but it has been found that some of these drugs act as vasodilators of retinal arteries. The exact mechanism behind the vasodilatory effect is not yet clear. Here we have addressed the issue by using small vessel myography to examine the effect of CAIs of the sulfonamide and coumarin type on the wall tension in isolated segments of porcine retinal arteries. Vessels were pre-contracted by the prostaglandin analog U-46619, and CAIs with varying affinity for five different carbonic anhydrase (CA) isoenzymes found in human tissue tested. We found that all compounds tested cause a vasodilation of pre-contracted retinal arteries, but with varying efficacy, as indicated by the calculated mean EC50 of each compound, ranging from 4.12 µM to 0.86 mM. All compounds had a lower mean EC50 compared to DZA. The dilation induced by benzolamide (BZA) and DZA was additive, suggesting that they may act on separate mechanisms. No clear pattern in efficacy and affinity for CA isoenzymes could be discerned from the results, although Compound 5, with a low affinity for all isoenzymes except the human (h) CA isoform IV, had the greatest potency, with the lowest EC50 and inducing the most rapid and profound dilation of the vessels. The results suggest that more than one isozyme of CA is involved in mediating its role in controlling vascular tone in retinal arteries, with a probable crucial role played by the membrane-bound isoform CA IV.

Characterization of the retina-induced relaxation in mice.

PURPOSE: The retinal relaxing factor (RRF) is a continuously released factor from the retina that causes vasorelaxation, the identity and potential role in physiology of which remain largely unknown. Experiments were performed to find out whether the RRF-induced relaxation is influenced by serotonin, glutamate, L-cysteine, the cytochrome P450 pathway, the cyclooxygenase pathway, or oxidative stress. In addition, the sensitivity of retinal and non-retinal arteries towards the RRF was compared. METHODS: In vitro tension measurements were performed on isolated mouse femoral or bovine retinal arteries to study the vasorelaxing effect of the RRF, induced by mouse or bovine retinas. RESULTS: The presence of serotonin, glutamate, or L-cysteine did not alter the RRF-induced relaxation. Increasing oxidative stress by hydroquinone and diethyldithiocarbamic acid sodium salt enhanced the RRF response. Inhibition of the cytochrome P450 or the cyclooxygenase pathway did not cause any alteration. Surprisingly, the RRF-induced relaxation was enhanced by the presence of flufenamic acid or carbenoxolone. Furthermore, bringing retinal tissue in close contact with retinal or non-retinal arteries induced comparable relaxations. CONCLUSIONS: Serotonin, glutamate, L-cysteine, the cytochrome P450, and the cyclooxygenase pathway do not influence the RRF-induced relaxation and the RRF-induced relaxation seems to be resistant to oxidative stress. The mechanism responsible for the enhanced RRF-induced relaxation in the presence of flufenamic acid or carbenoxolone remains elusive and the RRF does not show more effectivity on retinal arteries.

Thrombin-Induced Responses via Protease-Activated Receptor 1 Blocked by the Endothelium on Isolated Porcine Retinal Arterioles.

PURPOSE: Thrombin, a serine protease, causes organ-specific responses to vessels. However, the mechanism by which thrombin affects the retinal microcirculation remains unclear. We examined the effects of thrombin on the retinal microvasculature and signaling mechanisms. METHODS: Porcine retinal arterioles were isolated, cannulated, and pressurized (55 cmH2O) without flow in this in vitro study. Videomicroscopy techniques recorded changes in diameter in the retinal arterioles in response to thrombin at concentrations ranging from 0.001 to 20 mU/ml. RESULTS: Extraluminal administration of thrombin induced concentration-dependent vascular responses, that is, vasoconstriction at low concentrations less than 5 mU/ml and vasorelaxation with high concentrations greater than 5 mU/ml. However, intraluminal administration of thrombin (5 mU/m) did not constrict the retinal arterioles; in denuded vessels, intraluminal administration constricted the retinal arterioles. Thrombin-induced vasoconstriction was significantly (p < 0.01) suppressed by pretreatment with a protein kinase C (PKC) inhibitor and a protease-activated receptor (PAR)-1 inhibitor but not by PAR-2 and PAR-4 inhibitors or denudation. A rho kinase (ROCK) inhibitor also suppressed thrombin-induced vasoconstriction (5 mU/ml) compared with sodium nitroprusside. Endothelial denudation and pretreatment with an endothelial nitric oxide (NO) synthase inhibitor suppressed vasorelaxation caused by a high concentration of thrombin. CONCLUSIONS: A low concentration of thrombin causes vasoconstriction of smooth muscles via PAR-1, PKC, and ROCK, and a high concentration of thrombin possibly causes vasorelaxation of the retinal arterioles via nitric oxide synthase activation in the endothelium. The vascular endothelium might block signaling of thrombin-induced vasoconstriction in the retinal arterioles when administered intraluminally.

Acute Effect of Hypervolemic Hemodilution on Retrobulbar Hemodynamics in Anterior Ischemic Optic Neuropathy.

PURPOSE: Ischemic ocular disorders may be treated by hypervolemic hemodilution. The presumed therapeutic benefit is based on a volume effect and improved rheological factors. The aim was to investigate the acute effect of intravenous hydroxyethyl starch on retrobulbar hemodynamics in patients with nonarteritic anterior ischemic optic neuropathy (NAION). METHODS: 24 patients with acute NAION were included. Retrobulbar hemodynamics were measured using color Doppler imaging before and 15 min after intravenous infusion of 250 cc 10% hydroxyethyl starch (HES). Peak systolic velocity (PSV), end diastolic velocity (EDV), and Pourcelot's resistive index (RI) were measured in the ophthalmic artery (OA), central retinal artery (CRA), and short posterior ciliary arteries (PCAs). RESULTS: After infusion of HES blood flow velocities significantly increased in the CRA (PSV from 7.53 ± 2.33 to 8.32 ± 2.51 (p < 0.001); EDV from 2.16 ± 0.56 to 2.34 ± 0.55 (p < 0.05)) and in the PCAs (PSV from 7.18 ± 1.62 to 7.56 ± 1.55 (p < 0.01); EDV from 2.48 ± 0.55 to 2.66 ± 0.6 cm/sec (p < 0.01)). The RI of all retrobulbar vessels remained unaffected. Blood pressure and heart rate remained unchanged. CONCLUSIONS: Hypervolemic hemodilution has an acute effect on blood flow velocities in the CRA and PCAs in NAION patients. Increased blood flow in the arteries supplying the optic nerve head may lead to a better perfusion in NAION patients. This trial is registered with DRKS00012603.

Reperfusion of occluded branch retinal arteries by transluminal Nd:YAG laser embolysis combined with intravenous thrombolysis of urokinase.

PURPOSE: To report successful treatment with transluminal Nd:YAG laser embolysis (TYE) combined with urokinase thrombolysis for reperfusion of occluded branch retinal arteries with visible emboli. METHODS: A total of 34 eyes from 34 patients with acute, severe vision loss secondary to a branch retinal artery occlusion with visible emboli and retinal whitening were examined. Each patient was administered TYE therapy, which focused on the embolus, using an ocular contact lens; a 0.3-0.9 mJ laser pulse was delivered directly and gradually according to the reaction. Fundus photographs and fundus fluorescein angiography (FFA) were obtained before and immediately after the laser treatment. All patients received urokinase thrombolysis therapy drops intravenously for 5 days at 10-20 u/d. The follow-up period ranged from 6 to 14 months after therapy. The morphological characteristics of FFA associated with obstruction recovery of arterial fluorescence filling and visual function were analyzed. RESULTS: After TYE therapy, FFA examinations showed that the retinal artery and its branches exhibited completely restored blood flow without obstruction in 13 eyes, accounting for 38.2% of the cases. The blood flow was mostly recovered in 11 eyes (32.4% of patients). FFA examinations following the combined intravenous urokinase thrombolysis therapy showed that the retinal artery and its branches exhibited completely restored blood flow after obstruction in 16 eyes (47.1% of patients). The blood flow was mostly recovered in 15 eyes (44.1% of patients). CONCLUSION: TYE combined with urokinase thrombolysis is effective for reperfusion of occluded branch retinal arteries and improving visual recovery in patients with visible emboli.

EFFECTS OF INTRAVITREAL RANIBIZUMAB AND BEVACIZUMAB ON THE RETINAL VESSEL SIZE IN DIABETIC MACULAR EDEMA.

PURPOSE: The goal of this study was to assess the effects of a single injection of intravitreal ranibizumab (RAN) or bevacizumab (BEV) on the retinal vessel size in eyes with diabetic macular edema. MATERIALS AND METHODS: In total, 32 patients were enrolled in the RAN group, and 30 patients were included in BEV group. Each of these groups was also subdivided into two others groups: a study group and a control group. The study groups were composed of the injected eyes, whereas the noninjected fellow eyes served as the control groups. The patients underwent complete ophthalmic examinations, including optical coherence tomography and fundus fluorescein angiography, and the primary outcome measures included the central retinal artery equivalent, central retinal vein equivalent, and artery-to-vein ratio. RESULTS: In the RAN study group (n = 32), the preinjection mean central retinal artery equivalent (175.42 µm) decreased to 169.01 µm after 1 week, and to 167.47 µm after 1 month (P < 0.001), whereas the baseline central retinal vein equivalent (235.29 µm) decreased initially to 219.90 µm after 1 week, and to 218.36 µm after 1 month (P < 0.001). In the BEV study group (n = 30), the preinjection central retinal artery equivalent (150.21 µm) decreased to 146.25 µm after 1 week, and to 145.89 µm after 1 month (P < 0.001); whereas the baseline central retinal vein equivalent (211.87 µm) decreased initially to 204.59 µm after 1 week and was 205.24 µm after 1 month (P < 0.001). The preinjection artery-to-vein ratio values changed significantly (P = 0.001) after 1 week and after 1 month in the RAN group, but no significant alteration in the artery-to-vein ratio was observed in the BEV group (P = 0.433). In both the RAN (n = 32) and BEV (n = 30) control groups, none of the 3 parameters changed throughout the study period, when compared with the baseline. CONCLUSION: The results of this study showed that both RAN and BEV injections significantly constricted the retinal blood vessel diameters.

Probucol prevents the attenuation of ß2-adrenoceptor-mediated vasodilation of retinal arterioles in diabetic rats.

Probucol is an antihyperlipidemic drug with potent antioxidant properties. Oxidative stress plays an important role in the pathogenesis of diabetic retinopathy. In this study, we aimed to investigate the protective effects of probucol against diabetes-induced retinal vascular dysfunction in a rat model of diabetes. Diabetes was induced by a combination of streptozotocin treatment and D-glucose feeding, and retinal vasodilator responses were assessed by measuring the diameter of retinal arterioles. The vasodilator effect of salbutamol, a ß2-adrenoceptor agonist, on retinal arterioles was significantly diminished 2 weeks after the induction of diabetes. In non-diabetic rats, vasodilator responses to salbutamol were significantly reduced after an intravitreal injection of iberiotoxin, a blocker of large-conductance KCa (BKCa) channels. However, this effect was not observed in diabetic rats. Probucol had no significant effect on salbutamol-induced changes in diameter of retinal arterioles in non-diabetic rats, whereas it could prevent the attenuation of retinal vasodilator response to salbutamol in diabetic rats. These results suggest that the reduced function of BKCa channels is involved in the attenuation of ß2-adrenoceptor-mediated retinal vasodilation in diabetic rats. Probucol preserves the BKCa channel function in retinal arterioles under diabetic conditions; therefore, it may show beneficial effects on diabetic retinopathy by preventing or slowing the impairment of the retinal circulation in patients with diabetes mellitus.

Activation of Veratridine Sensitive Sodium Channels, But not Electrical Field Stimulation, Dilates Porcine Retinal Arterioles with Preserved Perivascular Tissue.

PURPOSE: Disturbances in retinal blood flow are a prominent feature of vision threatening retinal diseases. The regulation of tone in retinal resistance vessels involves the perivascular retinal tissue, but it is unknown to what extent neurons or glial cells contribute to the effect. Therefore, the purpose of the present study was to study the contribution of neurons in the perivascular retina to vascular tone during activation of voltage-gated sodium channels with veratridine and electrical field stimulation (EFS). METHODS: Porcine retinal arterioles with and without perivascular tissue were mounted in an isometric myograph system for studying the effects of the voltage-gated sodium channel opener veratridine and EFS on retinal vascular tone. RESULTS: Veratridine induced concentration-dependent relaxation of retinal arterioles which was more pronounced in arterioles with preserved perivascular retinal tissue than in isolated vessels. In the presence of this tissue, veratridine-induced relaxation was inhibited by the voltage-gated sodium channel blocker tetrodotoxin and the nitric oxide synthase inhibitor, Nω-Nitro-L-arginine methyl ester (L-NAME), but was unaffected by the inhibition of the cyclo-oxygenase inbitior ibuprofen and by blocking of adenosine receptors with 8-(p-Sulfophenyl)theophylline hydrate (8-PSPT). Electrical field stimulation induced no changes in retinal vascular tone. CONCLUSIONS: Sodium channels of neuronal origin are likely to be involved in the regulation of retinal vascular tone. The lack of effect of EFS on retinal vascular tone may be due to the lack of autonomic nerves in the retina.

Vessel diameter study: intravitreal vs posterior subtenon triamcinolone acetonide injection for diabetic macular edema.

PurposeTo detect and compare the vessel diameter effect of intravitreal vs subtenon injection of triamcinolone for diabetic macular edema (DME).MethodsSixty patients with DME who underwent triamcinolone injection either intravitreally (N=30) or under the tenon capsule (N=30) were included. Non-injected fellow eyes served as control. The main outcome measures were central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and artery-vein ratio (AVR).ResultsIn the intravitreal group, pre-injection mean CRAE (147.07 µ) decreased to 141.03 µ at 1 week and to 139.43 µ at 1 month (P<0.001) while baseline CRVE (209.61 µ) decreased initially to 198.85 µ at 1 week then to 198.49 µ at 1 month (P<0.001). In the subtenon group, pre-injection CRAE (152.18 µ) decreased to 149.49 µ at 1 week and to 147.47 µ at 1 month (P=0.017), while baseline CRVE (215.60 µ) decreased initially to 208.69 µ at 1 week then to 207.25 µ at 1 month (P=0.003). Pre-injection AVR values did not change at 1 week and at 1 month in both injection groups (P=0.66 and P=0.196, respectively). In the control group, none of the 3 parameters changed throughout the study period compared to the baseline (P>0.28).ConclusionIn eyes with DME, both intravitreal and subtenon triamcinolone injection led to a significant constriction of retinal arteries and veins.

Retrobulbar ocular blood flow changes measured by colour Doppler imaging after intra-arterial chemotherapy in retinoblastoma.

PURPOSE: To evaluate the effects of intra-arterial chemotherapy on retrobulbar blood flow parameters in patients with retinoblastoma. METHODS: 20 eyes of 10 patients with unilateral retinoblastoma that were treated with intra-arterial chemotherapy were evaluated using colour Doppler imaging. The peak systolic and end-diastolic velocities of the ophthalmic, central retinal and posterior ciliary arteries were determined. The pulsatility and resistance indices were calculated automatically. The treated eye was compared with the untreated (control) eye and with itself before and after intra-arterial chemotherapy. RESULTS: When comparing the retinoblastoma-containing eyes with the contralateral normal eyes, the peak systolic and end-diastolic velocities of the central retinal artery were significantly higher in the tumorous eyes than in the normal eyes before intra-arterial chemotherapy. Moreover, the peak systolic and end-diastolic velocities in the posterior ciliary and central retinal arteries were significantly decreased after intra-arterial chemotherapy in the tumorous eyes (p<0.05). There were no statistically significant differences in the other parameters. CONCLUSIONS: Our results suggest that intra-arterial chemotherapy has a measurable effect on the retrobulbar blood flow, which can cause a decrease in the peak systolic and end-diastolic velocities in the posterior ciliary and central retinal arteries.

Alk2/ACVR1 and Alk3/BMPR1A Provide Essential Function for Bone Morphogenetic Protein-Induced Retinal Angiogenesis.

OBJECTIVE: Increasing evidence suggests that bone morphogenetic protein (BMP) signaling regulates angiogenesis. Here, we aimed to define the function of BMP receptors in regulating early postnatal angiogenesis by analysis of inducible, endothelial-specific deletion of the BMP receptor components Bmpr2 (BMP type 2 receptor), Alk1 (activin receptor-like kinase 1), Alk2, and Alk3 in mouse retinal vessels. APPROACH AND RESULTS: Expression analysis of several BMP ligands showed that proangiogenic BMP ligands are highly expressed in postnatal retinas. Consistently, BMP receptors are also strongly expressed in retina with a distinct pattern. To assess the function of BMP signaling in retinal angiogenesis, we first generated mice carrying an endothelial-specific inducible deletion of Bmpr2. Postnatal deletion of Bmpr2 in endothelial cells substantially decreased the number of angiogenic sprouts at the vascular front and branch points behind the front, leading to attenuated radial expansion. To identify critical BMPR1s (BMP type 1 receptors) associated with BMPR2 in retinal angiogenesis, we generated endothelial-specific inducible deletion of 3 BMPR1s abundantly expressed in endothelial cells and analyzed the respective phenotypes. Among these, endothelial-specific deletion of either Alk2/acvr1 or Alk3/Bmpr1a caused a delay in radial expansion, reminiscent of vascular defects associated with postnatal endothelial-specific deletion of BMPR2, suggesting that ALK2/ACVR1 and ALK3/BMPR1A are likely to be the critical BMPR1s necessary for proangiogenic BMP signaling in retinal vessels. CONCLUSIONS: Our data identify BMP signaling mediated by coordination of ALK2/ACVR1, ALK3/BMPR1A, and BMPR2 as an essential proangiogenic cue for retinal vessels.

Pattern of omega-3 polyunsaturated fatty acid intake and fish consumption and retinal vascular caliber in children and adolescents: A cohort study.

We aimed to investigate whether fish and long chain omega-3 polyunsaturated fatty acid (LCn-3 PUFA) consumption changed appreciably during adolescence. We also assessed whether these dietary variables are associated with retinal microvascular signs (possible markers of future cardiovascular disease risk). 633 children had dietary data at ages 12 and 17. Fish and LCn-3 PUFA [eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA)] intake was assessed by a food frequency questionnaire. Retinal vessel caliber was quantified from digital photographs using computer software. Mean energy-adjusted intakes (mg/day) of total LCn-3 PUFA, EPA, and DHA at age 12 were 297.1±261.1; 102.5±106.9; and 129.7±137.7, respectively; and this increased significantly at age 17 to: 347.0±324.0 (p<0.0001); 122.5±132.7 (p = 0.0001); and 160.3±171.4 (p <0.0001), respectively. Increasing quartiles of LCn-3PUFA intake were associated with widening of mean retinal arteriolar caliber among 17-year old girls ~3.9 µm (multivariable-adjusted P-trend = 0.001). Girls who consumed ≥2 serves of fish/week versus those who did not had ~2.1 µm wider retinal arterioles (p = 0.03). No associations were observed among boys or with retinal venules. Mean dietary intakes of LCn-3 PUFA increased during adolescence, but are still below recommended levels of consumption. These results suggest that LCn-3 PUFA and fish intake might have a beneficial influence.

Dynamic functionality and static changes of retinal vessels in diabetic patients treated with intravitreal ranibizumab.

AIMS: To investigate the short-term effects of intravitreal ranibizumab on retinal vessel functionality in patients with diabetic macular edema (DME) by Dynamic Vessel Analyzer (DVA). METHODS: Patients presenting with DME were enrolled in the study. All patients underwent a complete ophthalmic evaluation, including optical coherence tomography and dynamic and static vessel analysis, using the DVA before (baseline), 1 week and 1 month after administration of intravitreal ranibizumab. DME subject were compared with diabetic retinopathy (DR) without DME subjects, and with normal non diabetic subjects (controls) matched for age and sex. RESULTS: A total of 45 eyes of 45 subjects (15 eyes for each group) were included in the analysis. In DME patients, dynamic analysis showed a significant decrease in mean arterial dilation from baseline to 1 week. Mean central retinal artery equivalent (CRAE) of DR patients without DME was significantly different from baseline and week 1 of DME eyes. In healthy control subjects, CRAE was significantly different from CRAE at baseline and 1 week on DME patients, but not significantly different from DR patients without DME. CONCLUSIONS: Using DVA in patients with DME, dynamic analysis showed a significant decrease in mean arterial dilation from baseline to 1 week in DME eyes. A significant reduction in arterial vessels could be demonstrated in DME patients compared to DR patients without DME and controls.

Three episodes of non-arteritic posterior ischemic optic neuropathy in the same patient treated with intravenous prostaglandin E1.

Non-arteritic posterior ischemic optic neuropathy (NA-PION) is a disorder involving reduced blood flow to the retrobulbar portion of the optic nerve. This disorder usually develops acutely, and research has suggested that high-dose steroid therapy soon after the onset of visual loss can result in significant visual improvement. This treatment, however, is not universally successful. The addition of a potent vasodilator could help to restore ocular blood flow. This case report describes the use of prostaglandin E1 (PGE1), a powerful vasodilator of the microcirculation, to treat three separate episodes of NA-PION over five years in the same patient. A 68-year-old white male was first seen in June 2009 with NA-PION in the left eye, and the condition was treated with steroids and PGE1. The patient had a subsequent episode in July 2010 that was treated with steroids and PGE1 and another in May 2014 that was treated with PGE1 alone. Visual acuity improved from 4/10 to 11/10 in 2009, from 4/10 to 11/10 in 2010, and from 5/10 to 10/10 in 2014. No complications due to the use of PGE1 were noted. PGE1 should be considered as a treatment for NA-PION to immediately restore blood flow and potentially improve vision.

[Assessing resveratrol effect on ocular blood flow in experiment].

AIM: To study the effect of resveratrol on ocular blood flow in vivo in healthy rats and those that underwent retinal ischemia/reperfusion. MATERIAL AND METHODS: The experimental study was performed on 40 Wistar rats (40 eyes). For ocular blood flow evaluation, color Doppler imaging (CDI), power Doppler (PD), and pulsed-wave spectral Doppler ultrasonography were performed using the Voluson E8 Expert ultrasonic diagnostic system (GE Healthcare). All rats were given resveratrol per os for 2 months of the study. Retinal ischemia/reperfusion injury was induced by a subconjunctival injection of endothelin-1. The control group included 10 intact animals. RESULTS: Signs of ischemic damage of the anterior and posterior eye segments were less pronounced in rats that were given resveratrol during both pre-ischemic (30 days) and post-ischemic (30 days) periods of follow-up. There was also a statistically significant increase in the peak systolic and end diastolic velocity of blood flow as well as a decrease in the resistive index of retrobulbar arteries in those rats that underwent ischemia/reperfusion as compared to the controls. CONCLUSION: Long-term resveratrol use (2 months) has proved effective in improving ocular blood flow in a rat model of retinal ischemia/reperfusion injury.