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Mechanisms of endothelial cell guidance and vascular patterning in the developing mouse retina.

The appropriate guidance and patterning of vessels during vascular development is critical for proper tissue function. The loss of these guidance mechanisms can lead to abnormal vascularization and a number of pathological conditions. The molecular basis of endothelial cell guidance and subsequent tissue specific vascular patterning remains largely unknown in spite of its clinical relevance and biological importance. In this regard, retinal vascular development offers many advantages for studying endothelial cell guidance and the mechanisms by which characteristic vascular patterns are formed. In this review, we will provide an overview of the known mechanisms that mediate vascular patterning during mouse retinal development, synthesizing these data to formulate a model of how growth factors, cellular adhesion molecules, and vascular-associated cells mediate directed endothelial cell migration and appropriate vascular remodeling. Finally, we will discuss the many aspects of retinal vascular development that remain unknown and cite evidence that many of these gaps may be addressed by further studying the guidance cues shared by vascular and neuronal elements in the retina and other parts of the central nervous system.

Animals↗

Development of traction retinal detachments following intravitreal injections of retinal Muller and pigment epithelial cells.

We injected varying numbers of retinal Muller glia into the rabbit vitreous in an established model of traction retinal detachment. We used indirect ophthalmoscopy to observe the changes elicited during the following 1 month. Although the severity of the tractional changes increased with increasing numbers of the glial cells, the pathology produced stabilized within the 1st week of injury. Muller glia were less effective at eliciting retinal detachments than retinal pigment epithelial cells (RPE) or mixtures of glia and RPE. Intravitreal tissue membranes derived from the glia differed morphologically from those derived from RPE. The glial membranes had fewer fibroblast-like cells, synthesized less extracellular matrix, and showed lower intravitreal cell proliferation, as determined by 3H-thymidine radioautography. Our findings indicate that membranes composed only of Muller glial cells promote less severe retinal pathology than those membranes composed of RPE or mixed cell types.

Animals↗

Rhegmatogenous retinal detachment with retinal telangiectasia.

A 34-year-old man with unilateral retinal telangiectasia developed a bullous retinal detachment. A horseshoe retinal tear was found at 12 o'clock. The detachment resolved with placement of an encircling scleral buckle. The prompt and permanent resolution of subretinal fluid supported our belief that this was a rhegmatogenous retinal detachment.

Adult↗

Evidence for self-absorption of terminals by developing axons of retinal ganglion cells in the chick.

The appearance of membrane-bound degenerative organelles in chick optic nerve axons was studied at the electron microscopic level. A semiquantitative analysis revealed a sharp increase in the number of axons containing accumulations of such organelles during the second day after hatching. In dark-reared chicks this increase was retarded, suggesting the presence of a light-influenced event in the early post-hatch period.

Animals↗

Coordinate activity in retinal and cortical development.

New approaches for detecting and manipulating patterns of neuronal activity have revealed diverse strategies for constructing circuits in the developing brain. Spontaneously generated patterns can provide activity-based information before the onset of sensory inputs. In addition to mechanisms based on chemical synaptic communication, coordination of activity via gap junctions can provide important cues for synchronous activity early in circuit formation.

Animals↗

Severe periphlebitis, peripheral retinal ischemia, and preretinal neovascularization in patients with multiple sclerosis.

Two patients with definite multiple sclerosis and marked retinal periphlebitis developed occlusive peripheral retinal vasculitis, which resulted in peripheral retinal ischemia and peripheral retinal neovascularization. Results of investigation for other causes of peripheral proliferative retinopathies were negative in both patients although one patient had a positive anticardiolipin antibody. Both patients have been followed up for over seven years and have maintained good visual acuity with mild regression of the preretinal neovascularization without laser intervention. An analysis of these two cases and six other reported cases indicates that severe periphlebitis can evolve into occlusive peripheral vasculitis, which results in peripheral retinal neovascularization in patients with multiple sclerosis.

Adult↗

Treatment of central retinal vein occlusion by injection of tissue plasminogen activator into a retinal vein.

PURPOSE: To report the injection of tissue plasminogen activator into a retinal vein to treat central retinal vein occlusion. METHODS: An 81-year-old woman with visual loss of the right eye secondary to central retinal vein occlusion developed central retinal vein occlusion and visual loss in her left eye. Treatment of her left eye with topical ocular hypotensive medications, pentoxifylline, and laser chorioretinal anastomosis was without benefit. Thereafter, she underwent vitreoretinal surgery, including tissue plasminogen activator injection into a branch retinal vein of her left eye. RESULTS: The patient reported subjective improvement in the vision of her left eye. Ophthalmoscopic and fluorescein angiographic improvement were also noted. CONCLUSION: The feasibility of cannulating a retinal vein for treatment has been demonstrated.

Aged↗

Aberrant melanosome development in the retinal pigmented epithelium of cats with Chediak-Higashi syndrome.

The Chediak-Higashi syndrome is a genetic disorder characterized by greatly enlarged cytoplasmic granules, including lysosomes and melanosomes. Eyes of humans and animals with Chediak-Higashi syndrome are hypopigmented to various degrees. Intraocular melanin granules vary in size, with some being massively enlarged. Electron microscopic examination of retinal pigmented epithelium of kittens with Chediak-Higashi syndrome disclosed a number of abnormalities of premelanosomes and melanosomes. Few premelanosomes were present. Most of the melanin granules were giant sized, but their structures varied. Some of the giant granules were composed of several premelanosomes and melanosomes in different stages of maturation. Others contained randomly oriented melanofilaments between melanosomes. There were also complex giant granules consisting of both melanosomal and lysosomal components. Inappropriate fusion of cytoplasmic granules appears to be the most likely mechanism for formation of the giant granules. Fusion of premelanosomes with lysosomes and resultant destruction of the premelanosomes probably is a major cause of the ocular hypopigmentation of Chediak-Higashi syndrome.

Aging↗

Development of normal retinal organization depends on Sonic hedgehog signaling from ganglion cells.

The adult retina is organized into three cellular layers--an outer photoreceptor, a middle interneuron and an inner retinal ganglion cell (RGC) layer. Although the retinal pigment epithelium (RPE) and Müller cells are important in the establishment and maintenance of this organization, the signals involved are unknown. Here we show that Sonic hedgehog signaling from RGCs is required for the normal laminar organization in the vertebrate retina.

Animals↗

VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization.

Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological retinal neovascularization. In the current paper, the mechanisms of physiological and pathological neovascularization are compared and contrasted. During pathological neovascularization, both the absolute and relative expression levels for VEGF164 increased to a greater degree than during physiological neovascularization. Furthermore, extensive leukocyte adhesion was observed at the leading edge of pathological, but not physiological, neovascularization. When a VEGF164-specific neutralizing aptamer was administered, it potently suppressed the leukocyte adhesion and pathological neovascularization, whereas it had little or no effect on physiological neovascularization. In parallel experiments, genetically altered VEGF164-deficient (VEGF120/188) mice exhibited no difference in physiological neovascularization when compared with wild-type (VEGF+/+) controls. In contrast, administration of a VEGFR-1/Fc fusion protein, which blocks all VEGF isoforms, led to significant suppression of both pathological and physiological neovascularization. In addition, the targeted inactivation of monocyte lineage cells with clodronate-liposomes led to the suppression of pathological neovascularization. Conversely, the blockade of T lymphocyte-mediated immune responses with an anti-CD2 antibody exacerbated pathological neovascularization. These data highlight important molecular and cellular differences between physiological and pathological retinal neovascularization. During pathological neovascularization, VEGF164 selectively induces inflammation and cellular immunity. These processes provide positive and negative angiogenic regulation, respectively. Together, new therapeutic approaches for selectively targeting pathological, but not physiological, retinal neovascularization are outlined.

Animals↗