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Morphological observations on the unique paired capillaries of the opossum retina.

Light-microscopic and ultrastructural analysis of the ocular tissues of the North American opossum (Didelphis virginiana) revealed that the arterial and venous segments of retinal vessels, including capillaries of the smallest calibre, occur in pairs. They do not form anastomotic networks, the common pattern in mammals with vascularised retinae, but instead the two segments of the pair join to form hairpin end loops. The paired vessels, with the arteriolar limb usually on the vitread aspect, penetrate the retina and branch to form three distinct layers of capillaries. The most superficial lies in the nerve fiber layer, the middle is situated in the inner nuclear layer and the deepest extends to the external limiting membrane, which is considerably deeper than in normal mammalian holangiotic retinae. The paired capillaries display classical morphological features of central nervous system capillaries, i.e., they are lined by continuous endothelial cells united by tight junctions. The lining endothelium is supported by a distinct basal lamina that splits to envelop pericytes. The latter, although abundant, are invariably interposed between the two vessels that form each vascular unit. Phylogenetic and functional aspects of this unique form of retinal vascularisation are discussed.

Animals↗

Relative photometric measurements of retinal circulation (dromofluorograms): a televison technique.

Television fluoroangiography is used in order to obtain fluorescein dilution curves (dromofluorograms [From the Greek word: epsilon rho omicron mu omicron, which means flowing. We coined this word because dilution curves do not afford a true measurement of the blood circulation, or simply of a dilution, but of the fluorescein transport in the circulation!] from single retinal vessels. An optical fiber conveys the light from a single retinal artery, vein, or any other retinal area on the video screen to a photomultiplier. After low-pass electronic filtration, the dilution curves are recorded on a strip-chart recorder. The measurements considered are all related to time: the time interval between initial instants of the arterial and venous curve; the time interval between maximum instants; the arterial and venous curve rising times. It is seen that (1) the method is sensitive enough to enable variations in the quantities in pathologic cases to be detected; (2) owing to the great variability from part to part of the vessels, it is important to specify where the retinal dromofluorogram has been recorded.

Collagen Diseases↗

The relationship of astrocyte-like cells to the vessels that contribute to the blood-ocular barriers.

Brain capillaries form a selective interface, the blood-brain barrier (BBB), between the neural parenchyma and the blood. The factors which regulate this interface are poorly understood. Both the iris and retina possess vascular beds that express some BBB characteristics; therefore, they provide attractive models to further our understanding of how blood-tissue interfaces are regulated. We have determined whether three BBB markers: the transferrin receptor, P-glycoprotein, and gamma-glutamyl transpeptidase (gamma-GTP), can be localized in the capillaries of the rat retina and iris. We have also compared, in retina and iris, the relationship which GFAP-positive cells have with the blood vessels to the expression of the three BBB markers by the vessels. Immunocytochemistry revealed that capillaries throughout the retina express P-glycoprotein and the transferrin receptor. Retinal vessels do not show detectable gamma-GTP activity. GFAP-positive cells ensheath capillaries in the nerve fibre layer of the retina. Of the three BBB characteristics we examined, iridial vessels expressed only one of them: P-glycoprotein. In the iris, GFAP-positive cells do not ensheath capillaries. From our results we conclude that all BBB characteristics do not have to be expressed and regulated in capillaries as a unit. Our results, in combination with those of earlier studies, suggest that the expression of some BBB features does not require intimate contact between capillaries and astrocytes or astrocyte-like cells. Barrier maintenance appears to be a complex process which involves the integration of several factors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Are retinal microvascular abnormalities associated with large artery endothelial dysfunction and intima-media thickness? The Hoorn Study.

It has been hypothesized that microvascular dysfunction affects endothelial dysfunction of the large arteries, which may explain the relationship of microvascular disease with macrovascular disease. The aim of the present study was to investigate the relationship of retinal microvascular disorders with endothelium-dependent FMD (flow-mediated vasodilatation) and carotid IMT (intima-media thickness). A total of 256 participants, aged 60-85 years, 70 with normal glucose metabolism, 69 with impaired glucose metabolism and 109 with Type II diabetes, were included in this study. All participants were ophthalmologically examined, including funduscopy and two field 45 degrees fundus photography, and were graded for retinal sclerotic vessel abnormalities and retinopathy. Retinal arteriolar and venular diameters were measured with a computer-assisted method. Brachial artery, endothelium-dependent FMD and carotid IMT were assessed ultrasonically as measurements of endothelial function and early atherosclerosis respectively. After adjustment for age, sex and glucose tolerance status, retinal vessel diameters, retinal sclerotic vessel abnormalities and retinopathy were not significantly associated with FMD. In contrast with other retinal microvascular abnormalities, retinal venular dilatation was associated with increased IMT [standardized beta value (95% confidence interval), 0.14 (0.005-0.25)]. This association was attenuated and lost statistical significance after adjustment for cardiovascular risk factors, in particular after correction for fasting insulin. In the present study, retinal microvascular disorders are not independently associated with impaired FMD. In addition, retinal venular dilatation is associated with increased IMT, although non-significantly after multivariable adjustment for cardiovascular risk factors. Therefore our data provide evidence that retinal microvascular disease is of limited value in risk stratification for future cardiovascular events.

Aged↗

Ocular findings in ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome.

PURPOSE: To report the ocular findings in two siblings with IFAP and their mother and to review the natural course of the keratopathy of this disease. METHODS: Clinical ophthalmological examination of all patients and fundus photography of the carrier mother were performed. RESULTS: Both affected male children had severe photophobia, total superficial and deep corneal vascularization, and reduction of vision to counting fingers.The mother had tortuous retinal vessels. CONCLUSIONS: Males with IFAP have an inexorable progression of corneal vascularization and loss of vision. Retinal vascular tortuosity may be another clinical sign of carrier status in females.

Abnormalities, Multiple↗

Retrolental fibroplasia: evidence for a role of the prostaglandin cascade in the pathogenesis of oxygen-induced retinopathy in the newborn beagle.

Aspirin administration, at a dosage producing plasma levels within the human therapeutic range, caused marked inhibition of production of both vascular prostacyclin (a vasodilator) and platelet thromboxane (a vasoconstrictor) in beagle puppies. In addition, aspirin-treated, oxygen-exposed puppies developed retinopathy of significantly greater severity than their unmedicated, oxygen-exposed littermates. Direct ophthalmoscopic observations indicated that whereas sustained oxygen breathing produced retinal vasoconstriction in unmedicated puppies, retinal vessels of aspirin-treated littermates became more dilated or remained unchanged. It is postulated that retinal vasoconstriction may be a normal physiologic mechanism to protect the immature retina from damaging effects of high blood oxygen levels; i.e., it may be a protective rather than a pathologic process in response to hyperoxia. Many vascular anomalies which characterize the human disease were present in the retinas of the puppies. Several of the most severely affected puppies treated with aspirin even displayed grade III cicatricial retinopathy (falciform retinal fold). Thus, a major criticism of the retrolental fibroplasia animal model has been addressed by producing cicatricial retrolental fibroplasia in puppies, and the confidence with which results from experimental animal studies might be extrapolated to the clinical situation is thereby strengthened.

Animals↗

Ultrastructural and biochemical studies on the neuroprotective effects of excitatory amino acid antagonists in the ischemic rat retina.

The effects of glutamate receptor agonists were evaluated, by utilizing the electron microscope, in a photothrombotic occlusion model of rat retinal vessels in order to study the ischemic damage and its antagonism in each morphologically identified population of retinal neurons. Rats were systemically injected with rose bengal fluorescein dye and one of their eyes was then exposed to bright light. This treatment caused neuronal damage and reduced the activities of the neuronal marker enzymes, choline acetyltransferase and glutamate decarboxylase, by approximately 75%. A single intravitreal injection of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzoquinoxaline (NBQX, 10-50 nmol), an antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, or of thiokynurenate (100-400 nmol), which also antagonizes N-methyl-D-aspartate (NMDA) receptors, performed immediately after the lesion, significantly reduced this loss. The electron microscope examination showed major damage in each type of retinal neuron, the pigment epithelium, and the microvessels. NBQX or thiokynurenic acid reduced, in a comparable manner, the effects of ischemia on the pigment epithelium, the photoreceptors, and the bipolar and the horizontal cells. NBQX was particularly efficient in reducing the damage to the amacrine cells located in the inner nuclear layer. The displaced amacrine and ganglion cells were not protected by NBQX but were almost completely spared in animals treated with thiokynurenate. These results show that antagonism of AMPA receptors is sufficient to reduce ischemic damage in a large number of retinal neurons, but that neuroprotection in the ganglion cell layer may be obtained only with agents which also antagonize NMDA receptors.

Animals↗

Preserved vision in a case of morning glory syndrome: some pertinent questions.

Morning glory syndrome, an unusual developmental anomaly of the optic nerve head, presenting with funnelled enlargement of the disc with a white dot in the centre and a peripheral vascular pattern along the disc margin, with features of typical entry and exit of retinal vessels on the optic nerve head and exceptionally good vision in the involved eye with old traumatic retinal detachment in the other, in a young Indian girl is described here for its rarity and indifferent clinical presentation. Various factors in its pathogenesis are postulated.

Adolescent↗

Reduction in shear stress, activation of the endothelium, and leukocyte priming are all required for leukocyte passage across the blood--retina barrier.

The passage of leukocytes across the blood-retina barrier at the early stages of an inflammatory reaction is influenced by a complex series of interactions about which little is known. In particular, the relationship between hydrodynamic factors, such as shear stress and leukocyte velocity, to the adherence and subsequent extravasation of leukocytes into the retina is unclear. We have used a physiological method, scanning laser ophthalmoscopy, to track labeled leukocytes circulating in the retina, followed by confocal microscopy of retinal flatmounts to detect infiltrating cells at the early stage of experimental autoimmune uveitis. This has shown that retinal vessels are subjected to high shear stress under normal circumstances. During the inflammatory reaction, shear stress in retinal veins is reduced 24 h before leukocyte infiltration. This reduction is negatively correlated with leukocyte rolling and sticking in veins and postcapillary venules, the sites of leukocyte extravasation. Activation of vascular endothelial cells is also a prerequisite for leukocyte rolling and infiltration. In addition, antigen priming of leukocytes is influential at the early stage of inflammation, and this is seen clearly in the reduction in rolling velocity and adherence of the primed leukocytes in activated retinal venules, 9 days postimmunization.

Animals↗

Abnormal retinal vascular morphology in young adults following intrauterine growth restriction.

OBJECTIVE: Intrauterine growth restriction (IUGR) resulting in low birth weight for gestational age may predispose one to development of cardiovascular disease later in life. Abnormal fetal blood flow in the presence of fetal growth restriction helps to distinguish infants with true fetal growth impairment from small but normal infants. Our goal was to investigate associations between IUGR with abnormal fetal blood flow and abnormal retinal vascular morphology at 18 years of age. METHODS: A prospective study was performed with 21 subjects with IUGR (abnormal fetal aortic blood flow velocity; birth weight small for gestational age; median birth weight deviation from the population mean of -31% [range: -22% to -42%] and in 23 subjects with birth weight appropriate for gestational age [normal fetal aortic blood flow velocity; median birth weight deviation of -2% (range: -10% to 22%)]). The retinal vessel morphology was evaluated by digital image analysis. RESULT: Subjects with IUGR (n = 21) had significantly less retinal vascularization as evidenced by a lower number of vascular branching points (median: 26; range: 20-31) as compared with the subjects who were born appropriate for gestational age (median: 28; range: 26-32). Within the entire group (N = 44), increasing negative birth weight deviation was associated with a reduced number of vascular branching points (r = 0.36. CONCLUSION: Our findings show that IUGR with abnormal fetal blood flow is associated with abnormal retinal vascular morphology in young adult life.

Adolescent↗

Reversible retinal vasospasm in magnesium-treated hypertension despite no significant change in blood pressure.

8 young, untreated, hypomagnesemic patients with a recent onset of high-renin essential hypertension, were treated with 750 mg Mg oxide daily. Only functional (vasospastic) lesions were observed in their retinal vessels. After 3 months of therapy, despite no significant change in blood pressure, complete reversal of the retinal changes was observed. The retinal vascular changes could be attributable to vasospasm secondary to hypomagnesemia since serum Mg levels normalized during treatment.

Humans↗

Macular involvement in morning glory syndrome.

Clinical features of morning glory syndrome were studied in 8 eyes of 7 patients. The cases were divided into two groups according to the size of the elevated peripapillary white ring. The size of the ring was expressed as an average disk diameter of normal control eyes. In 2 eyes of Group I with the ring less than 2.0 disk diameters, white tissue on the disk was less pronounced than in Group II, and vascular pattern in the posterior retina was almost normal. The macular ring reflex was present. In 6 eyes of Group II with the ring exceeding 2.0 disk diameters, white tissue on the disk was more marked than in Group I, and retinal vessels were narrow and extended straight toward the midperiphery. the macula was not formed, but a yellowish retinal area was observed on the center or temporal part of the elevated peripapillary white ring. It was concluded that in morning glory syndrome the macula may often by involved when anomaly of the optic disk is remarkable.

Adolescent↗

Endothelial survival factors and spatial completion, but not pericyte coverage of retinal capillaries determine vessel plasticity.

Pericyte loss and capillary regression are characteristic for incipient diabetic retinopathy. Pericyte recruitment is involved in vessel maturation, and ligand-receptor systems contributing to pericyte recruitment are survival factors for endothelial cells in pericyte-free in vitro systems. We studied pericyte recruitment in relation to the susceptibility toward hyperoxia-induced vascular remodeling using the pericyte reporter X-LacZ mouse and the mouse model of retinopathy of prematurity (ROP). Pericytes were found in close proximity to vessels, both during formation of the superficial and the deep capillary layers. When exposure of mice to the ROP was delayed by 24 h, i.e., after the deep retinal layer had formed [at postnatal (p) day 8], preretinal neovascularizations were substantially diminished at p18. Mice with a delayed ROP exposure had 50% reduced avascular zones. Formation of the deep capillary layers at p8 was associated with a combined up-regulation of angiopoietin-1 and PDGF-B, while VEGF was almost unchanged during the transition from a susceptible to a resistant capillary network. Inhibition of Tie-2 function either by soluble Tie-2 or by a sulindac analog, an inhibitor of Tie-2 phosphorylation, resensitized retinal vessels to neovascularizations due to a reduction of the deep capillary network. Inhibition of Tie-2 function had no effect on pericyte recruitment. Our data indicate that the final maturation of the retinal vasculature and its resistance to regressive signals such as hyperoxia depend on the completion of the multilayer structure, in particular the deep capillary layers, and are independent of the coverage by pericytes.

Angiopoietin-1↗

Permeability of blood-ocular barriers of neonatal and adult cats to fluorescein-labeled dextrans of selected molecular sizes.

The permeability of the ocular blood vessels and neuroepithelial layers (the blood-ocular barriers) to fluorescein-labeled dextrans of selected molecular sizes was evaluated in neonatal and adult cats by fluorescence microscopy. The iris and ciliary process vessels were permeable to molecules as large as 85A effective diffusion radius (EDR). In the kitten, the choriocapillaris was permeable to molecules as large as 58A EDR, and in the adult to molecules only as large as 32A EDR. The retinal vessels and the retinal pigment epithelium were impermeable to all markers. The role of the cat's iris vessel in aqueous humor formation appears dissimilar to that of other species in that molecules larger than serum proteins traverse the walls of the iris capillaries.

Animals↗

Rhythmic changes in velocity, volume, and flow of blood in the optic nerve head tissue.

Using laser Doppler flowmetry, slow variations in velocity, volume, and flux of red blood cells in the optic nerve head (ONH), choroid, and retina of the anesthetized minipig have been demonstrated. The variations of velocity and volume were highly regular and vigorous in the ONH and had frequencies ranging from 2.5 to 4.5 cycles/min. The flux variations were smaller or absent due to a phase shift of approximately 180 degrees between the volume and velocity changes. The volume fluctuations were synchronized to those of the PO2 measured in the vitreous, at approximately 50 microns from the surface of the ONH tissue. The fluctuations were less regular in the choroidal and the retinal vessels and their frequencies were higher than those in the ONH. The lack of correlation between the fluctuations in the ONH and those in the retinal and choroidal vessels points toward a local mechanism. The changes in blood volume in the ONH, the phase shift between volume and velocity changes, and the predominance of venules at the surface of the ONH are three factors suggesting that this mechanism involves a change in the diameter of the venules rather than in the arterioles.

Animals↗

Lack of collagen XVIII/endostatin results in eye abnormalities.

Mice lacking collagen XVIII and its proteolytically derived product endostatin show delayed regression of blood vessels in the vitreous along the surface of the retina after birth and lack of or abnormal outgrowth of retinal vessels. This suggests that collagen XVIII/endostatin is critical for normal blood vessel formation in the eye. All basement membranes in wild-type eyes, except Descemet's membrane, showed immunogold labeling with antibodies against collagen XVIII. Labeling at sites where collagen fibrils in the vitreous are connected with the inner limiting membrane and separation of the vitreal matrix from the inner limiting membrane in mutant mice indicate that collagen XVIII is important for anchoring vitreal collagen fibrils to the inner limiting membrane. The findings provide an explanation for high myopia, vitreoretinal degeneration and retinal detachment seen in patients with Knobloch syndrome caused by loss-of-function mutations in collagen XVIII.

Angiogenesis Inhibitors↗

Effects of optic atrophy on retinal blood flow and oxygen saturation in humans.

Retinal blood flow and oxygen saturation were evaluated in patients with unilateral inner retinal degeneration secondary to neurogenic optic atrophy. Arteriovenous O2 saturation for temporal and nasal vascular segments of the affected eyes, evaluated by retinal vessel oximetry, was 12% +/- 9% higher than in the fellow eyes (seven patients). Blood flow in the temporal retinal arteries of the affected eyes, measured by the laser Doppler technique, was 48% +/- 20% lower than in the fellow eyes (four patients). The combination of these results indicated a 40% +/- 29% reduction in O2 delivery in the affected eyes (four patients), thereby quantifying the decrease in retinal metabolism that resulted from inner retinal degeneration.

Adolescent↗

Retinopathy associated with acute pancreatitis.

Two patients (a 28-year-old woman and a 23-year-old man) with acute pancreatitis developed severe visual loss. The acute stage of retinopathy consisted of retinal edema, cotton-wool patches, and retinal hemorrhages, predominantly in the posterior pole of both eyes. During the five-year follow-up period, visual acuity improved and sequential fluorescein angiography of both patients demonstrated reperfusion of previously occluded retinal vessels. After resolution of the cotton-wool patches, the previously edematous areas were replaced by foci of retinal thinning which created irregularities in the internal limiting membrane light reflex. Visual fields demonstrated scotomas corresponding to the areas of the previous cotton-wool patches.

Acute Disease↗