Angiogenesis is a complex biologic process that occurs normally in development and in turnover and remodeling of mature vascular networks. Pathological angiogenesis and neovascularization occur in association with retinal and ocular ischemic diseases, in retinopathy of prematurity and other developmental disorders, and in tumor growth and metastasis. We describe current understanding of cellular and molecular mechanisms of retinal vascular development, highlighting aspects that relate to eye diseases, that provide sites of therapeutic intervention in ophthalmology and that are potential avenues for research.

Animals↗

PubMedDate not supplied

Discrete reduction patterns of parvalbumin and calbindin D-28k immunoreactivity in the dorsal lateral geniculate nucleus and the striate cortex of adult macaque monkeys after monocular enucleation.

We analyzed the immunohistochemical distribution of the two calcium-binding proteins, parvalbumin (PV) and calbindin D-28k (CB), in the primary visual cortex and lateral dorsal geniculate nucleus (dLGN) of monocularly enucleated macaque monkeys (Macaca fascicularis and Macaca nemestrina) in order to determine how the expression of PV and CB is affected by functional inactivity. The monkeys survived 1-17 weeks after monocular enucleation. The distribution pattern of each of the proteins was examined immunocytochemically using monoclonal antibodies and compared with that of the metabolic marker cytochrome oxidase (CO). We recorded manually the number of immunostained neurons and estimated the concentration of immunoreactive staining product using a computerized image-acquisition system. Our results indicate a decrease of approximately 30% in the labeling of PV-immunoreactive (ir) neuropil particularly in those layers of denervated ocular-dominance columns receiving the geniculocortical input. There was no change in the number of PV-ir neurons in any compartment irrespective of the enucleation interval. For CB-ir, we found a 20% decrease in the neuropil labeling in layer 2/3 of the denervated ocular-dominance columns. In addition, a subset of pyramidal CB-ir neurons in layers 2 and 4B, which are weakly stained in control animals, showed decreased labeling. In the dLGN of enucleated animals, PV-ir and CB-ir were decreased only in the neuropil of the denervated layers. From these results, we conclude that cortical interneurons and geniculate projection neurons still express PV and CB in their cell bodies after disruption of the direct functional input from one eye. The only distinct decrease of PV and CB expression is seen in axon terminals from retinal ganglion cells in the dLGN, and in the axons and terminals of both geniculocortical projection cells and cortical interneurons in the cerebral cortex.

Animals↗

PubMedDate not supplied

Expression of glycine and the glycine transporter glyt-1 in the developing rat retina.

Previous studies show that glycine transporter-1 (glyt-1) is a consistent membrane marker of adult retinal neurons that are likely to release glycine at their synaptic terminals (Pow, 1998; Vaney et al., 1998; Pow & Hendrickson, 1999). The current study investigated when glyt-1 immunoreactivity appeared in the postnatal rat retina, and whether all glycine-containing neurons also labelled for glyt-1. Ganglion cells, horizontal cells, and photoreceptors showed transient labelling. Many cells in the ganglion cell layer are immunoreactive for both glycine and glyt-1 at postnatal day (Pd) 1 but both are minimal by Pd5. Transient immunoreactivity for both glyt-1 and glycine was observed in presumptive horizontal cells between Pd5 and Pd10. At Pd1 many cells in the outer part of the retina which resembled immature photoreceptors were heavily labelled for glycine, but did not express glyt-1; these disappeared at older ages. These findings suggest diverse mechanisms and transient roles for glycine in the developing rat retina. In the adult rat retina, a subpopulation of amacrine cells are prominently immunoreactive for both glycine and glyt-1. These cells labelled for glycine at Pd1, but did not express significant levels of glyt-1 until Pd5. Processes from these amacrine cells did not reach the inner half of the inner plexiform layer until Pd10-14. Bipolar cells became glycine-IR between Pd10 and Pd14, but consistently lacked any glyt-1 immunoreactivity. This temporal pattern of labelling strongly indicates that bipolar cells label for glycine when gap junctions become functional between glycine/glyt-1 immunoreactive amacrine cells and cone bipolar cells.

Amino Acid Transport Systems, Neutral↗

PubMedDate not supplied

Development of the primate area of high acuity. 1. Use of finite element analysis models to identify mechanical variables affecting pit formation.

Most primate retinas have an area dedicated for high visual acuity called the fovea centralis. Little is known about specific mechanisms that drive development of this complex central retinal specialization. The primate area of high acuity (AHA) is characterized by the presence of a pit that displaces the inner retinal layers. Virtual engineering models were analyzed with finite element analysis (FEA) to identify mechanical mechanisms potentially critical for pit formation. Our hypothesis is that the pit emerges within the AHA because it contains an avascular zone (AZ). The absence of blood vessels makes the tissue within the AZ more elastic and malleable than the surrounding vascularized retina. Models evaluated the contribution to pit formation of varying elasticity ratios between the AZ and surrounding retina, AZ shape, and width. The separate and interactive effects of two mechanical variables, intraocular pressure (IOP) and ocular growth-induced retinal stretch, on pit formation were also evaluated. Either stretch or IOP alone produced a pit when applied to a FEA model having a highly elastic AZ surrounded by a less elastic region. Pit depth and width increased when the elasticity ratio increased, but a pit could not be generated in models lacking differential elasticity. IOP alone produced a deeper pit than did stretch alone and the deepest pit resulted from the combined effects of IOP and stretch. These models predict that the pit in the AHA is formed because an absence of vasculature makes the inner retinal tissue of the AZ very deformable. Once a differential elasticity gradient is established, pit formation can be driven by either IOP or ocular growth-induced retinal stretch.

Animals↗

PubMedDate not supplied

Development of the primate area of high acuity. 2. Quantitative morphological changes associated with retinal and pars plana growth.

Mechanisms underlying the development of the primate area of high acuity (AHA) remain poorly understood. Finite-element models have identified retinal stretch and intraocular pressure (IOP) as possible mechanical forces that can form a pit (Springer & Hendrickson, 2004). A series of Macaca nemestrina monkey retinas between 68 days postconception (dpc) and adult were used to quantify growth and morphological changes. Retinal and pars plana length, optic disc diameter, disc-pit distance, and inner and outer retinal laminar thickness were measured over development to identify when and where IOP or stretch might operate. Horizontal optic disc diameter increased 500 mum between 115 dpc and 2 months after birth when it reached adult diameter. Disc growth mainly influences the immediate surrounding retina, presumably displacing retinal tissue centrifugally. Pars plana elongation also began at 115 dpc and continued steadily to 3-4 years postnatal, so its influence would be relatively constant over retinal development. Unexpectedly, horizontal retinal length showed nonlinear growth, divided into distinct phases. Retinal length increased rapidly until 115 dpc and then remained unchanged (quiescent phase) between 115-180 dpc. After birth, the retina grew rapidly for 3 months and then very slowly into adulthood. The onset of pit development overlapped the late fetal quiescent phase, suggesting that the major mechanical factor initiating pit formation is IOP, not retinal growth-induced stretch. Developmental changes in the thickness of retinal layers were different for inner and outer retina at many, but not all, of the ten eccentricities examined.

Animals↗

PubMedDate not supplied

Development of the primate area of high acuity, 3: temporal relationships between pit formation, retinal elongation and cone packing.

By establishing an avascular, highly elastic, region within the fetal area of high acuity (AHA), the developing primate eye has created a unique substrate on which the mechanical forces of intraocular pressure (IOP) and growth-induced retinal stretch (stretch) can act. We proposed (Springer & Hendrickson, 2004b) that these forces generate both the pit and high cone density found in the adult AHA. In this paper, we use quantitative measures to determine the temporal relationships between nasal and temporal retinal elongation, changes in pit depth, cone packing, and cone morphology over M. nemestrina retinal development. Retinal length increased rapidly to about 105 days postconception (dpc; Phase 1) and then elongation virtually ceased (Phase 2) until just after birth (180 dpc). Retinal elongation due to stretch resumed during Phase 3 until approximately 315 dpc (4-5 months), after which time the retina appeared mature (Phase 4). The pit appeared during the quiescent Phase 2, suggesting that IOP acts, in conjunction with molecular changes in the inner retina, on the highly elastic, avascular, AHA to generate a deep, narrow pit and causes inner retinal cellular displacements. Subsequently (Phase 3), the pit widened, became 50% shallower and central inner retinal lamina thinned slightly due to a small amount of retinal stretch occurring in the AHA. Centripetal movement of cones was minimal until just after birth when the pit reached 88% of its maximal depth. Accelerated cone packing during Phase 3 was temporally correlated with increased stretch.

Animals↗

PubMedDate not supplied

Distribution of the glycine transporter glyt-1 in mammalian and nonmammalian retinae.

We have examined the distribution of the glycine transporter glyt-1 in retinae of macaques, cats, rabbits, rats, and chickens. In all species, all glycine-containing amacrine cells expressed immunoreactivity for glyt-1, though the intensity of immunoreactivity for glyt-1 did not appear to directly correlate with the intensity of immunoreactivity for glycine in individual cells. A small subpopulation of glycine-immunoreactive displaced amacrine cells or ganglion cells also expressed glyt-1 in retinae from macaques, cats, chickens, and rats but not in retinae from rabbits. In addition, in all species examined, some displaced amacrine cells also contained glycine but did not express glyt-1. In monkeys, cats, and rats, populations of cells which we interpret as being glycine-containing interplexiform cells expressed glyt-1: these cells lacked a content of glutamate, suggesting they are not bipolar cells. The glycine-containing bipolar cells did not express glyt-1, suggesting that these cells probably acquired their content of glycine by other means such as via gap junctional connections with glycine-containing amacrine cells.

Amino Acid Transport Systems, Neutral↗

PubMedDate not supplied

Expression of glycine and the glycine transporter Glyt-1 in the developing rat retina.

Previous studies show that glycine transporter-1 (glyt-1) is a consistent membrane marker of adult retinal neurons that are likely to release glycine at their synaptic terminals (Pow, 1998; Vaney et al., 1998; Pow & Hendrickson, 1999). The current study investigated when glyt-1 immunoreactivity appeared in the postnatal rat retina, and whether all glycine-containing neurons also labelled for glyt-1. Ganglion cells, horizontal cells, and photoreceptors showed transient labelling. Many cells in the ganglion cell layer are immunoreactive for both glycine and glyt-1 at postnatal day (Pd) 1 but both are minimal by Pd5. Transient immunoreactivity for both glyt-1 and glycine was observed in presumptive horizontal cells between Pd5 and Pd10. At Pd1 many cells in the outer part of the retina which resembled immature photoreceptors were heavily labelled for glycine, but did not express glyt-1 these disappeared at older ages. These findings suggest diverse mechanisms and transient roles for glycine in the developing rat retina. In the adult rat retina, a subpopulation of amacrine cells are prominently immunoreactive for both glycine and glyt-1. These cells labelled for glycine at Pd1, but did not express significant levels of glyt-1 until Pd5. Processes from these amacrine cells did not reach the inner half of the inner plexiform layer until Pd10-14. Bipolar cells became glycine-IR between Pd10 and Pd14, but consistently lacked any glyt-1 immunoreactivity. This temporal pattern of labelling strongly indicates that bipolar cells label for glycine when gap junctions become functional between glycine/glyt-1 immunoreactive amacrine cells and cone bipolar cells.

Amino Acid Transport Systems, Neutral↗