The cytoplasmic domain of neuropilin 1 is dispensable for angiogenesis, but promotes the spatial separation of retinal arteries and veins.

Neuropilin 1 (NRP1) is a transmembrane glycoprotein that is essential for blood vessel development in vertebrates. Best known for its ability to bind members of the vascular endothelial growth factor (VEGF) and class 3 semaphorin families through its extracellular domain, it also has a highly conserved cytoplasmic domain, which terminates in a SEA motif that binds the PDZ protein synectin/GIPC1/NIP. Previous studies in zebrafish embryos and tissue culture models raised the possibility that the SEA motif of NRP1 is essential for angiogenesis. Here, we describe the generation of mice that express a form of NRP1 that lacks the cytoplasmic domain and, therefore, the SEA motif (Nrp1(cyto)(Δ)(/)(Δ) mice). Our analysis of pre- and perinatal vascular development revealed that vasculogenesis and angiogenesis proceed normally in these mutants, demonstrating that the membrane-anchored extracellular domain is sufficient for vessel growth. By contrast, the NRP1 cytoplasmic domain is required for normal arteriovenous patterning, because arteries and veins crossed each other at an abnormally high frequency in the Nrp1(cyto)(Δ)(/)(Δ) retina, as previously reported for mice with haploinsufficient expression of VEGF in neural progenitors. At crossing sites, the artery was positioned anteriorly to the vein, and both vessels were embedded in a shared collagen sleeve. In human eyes, similar arteriovenous crossings are risk factors for branch retinal vein occlusion (BRVO), an eye disease in which compression of the vein by the artery disrupts retinal blood flow, causing local tissue hypoxia and impairing vision. Nrp1(cyto)(Δ)(/)(Δ) mice may therefore provide a suitable genetic model to study the aetiology of BRVO.

Retina-specific activation of a sustained hypoxia-like response leads to severe retinal degeneration and loss of vision.

Loss of vision and blindness in human patients is often caused by the degeneration of neuronal cells in the retina. In mouse models, photoreceptors can be protected from death by hypoxic preconditioning. Preconditioning in low oxygen stabilizes and activates hypoxia inducible transcription factors (HIFs), which play a major role in the hypoxic response of tissues including the retina. We show that a tissue-specific knockdown of von Hippel-Lindau protein (VHL) activated HIF transcription factors in normoxic conditions in the retina. Sustained activation of HIF1 and HIF2 was accompanied by persisting embryonic vasculatures in the posterior eye and the iris. Embryonic vessels persisted into adulthood and led to a severely abnormal mature vessel system with vessels penetrating the photoreceptor layer in adult mice. The sustained hypoxia-like response also activated the leukemia inhibitory factor (LIF)-controlled endogenous molecular cell survival pathway. However, this was not sufficient to protect the retina against massive cell death in all retinal layers of adult mice. Caspases 1, 3 and 8 were upregulated during the degeneration as were several VHL target genes connected to the extracellular matrix. Misregulation of these genes may influence retinal structure and may therefore facilitate growth of vessels into the photoreceptor layer. Thus, an early and sustained activation of a hypoxia-like response in retinal cells leads to abnormal vasculature and severe retinal degeneration in the adult mouse retina.

Smaller birth size is associated with narrower retinal arterioles in early adolescence.

OBJECTIVE: In the current study, we aimed to examine the associations of low birth weight with retinal vascular caliber and vascular fractal dimension during early adolescence. METHODS: A population-based study of 12-year-old schoolchildren (2353/3144 [75.3%]) recruited from a random cluster sample of 21 schools. Birth weight, birth length and head circumference were obtained via parent report of the child's birth record. Retinal images were taken and vessel diameter and fractal dimension were quantified using validated computer-based methods. RESULTS: After adjusting for age, sex, ethnicity, body mass index, iris color, axial length, mean arterial blood pressure, prematurity and fellow retinal vascular caliber, children in the lowest quartiles of birth weight had ∼2.5 µm narrower mean retinal arteriolar caliber than those in the highest quartiles (p for trend = 0.001). Associations were observed between shorter birth length and smaller head circumference with narrower retinal arterioles. Smaller head circumference was associated with decreased fractal dimension (p for trend = 0.03). CONCLUSIONS: Children with lower birth weight were more likely to have narrower retinal arterioles, while those with smaller head circumference were more likely to have reduced complexity of their retinal microvasculature. These variations in microvascular structure in adolescence could reflect a susceptibility to cardiovascular disease during adulthood, resulting from a disadvantaged growth environment in utero.

[Prepapillary arterial loop and retinal arterial branch occlusion]. / Une boucle artérielle prépapillaire compliquée d'occlusion de branche artérielle rétinienne.

Preretinal arterial loops are congenital vascular anomalies that originate from a main branch of the central retinal artery on the optic disc. These arterial loops are usually unilateral and asymptomatic, but they can be associated with retinal artery branch occlusion. We report one case of inferior temporal retinal artery occlusion in a patient with preretinal arterial loops. Two different mechanisms are thought to be the cause of occlusion: twisting of the loop or thrombosis.

The central retinal artery and regression of the hyaloid artery in perinatal cattle.

The arterial supply to the retina and lens of 10 fetal, 10 neonatal and four adult Zavot-bred cattle of both sexes was studied macroscopically and by stereoscopic microscopy by means of vascular perfusion with latex, giving special emphasis on the hyaloid artery. The central retinal artery ramified in four major retinal arterioles, which formed a compact network throughout the retina (holangiotic or euangiotic pattern). The hyaloid artery was patent in all fetal stages and extended through the vitreous cavity of the eye to the caudal surface of the capsule of the lens. Atrophy of the hyaloid artery began immediately after birth and was completed on day 17 after parturition. No remnant of the hyaloid artery in the vitreous cavity was observed in the adult cattle examined at stereoscopic microscopic level.

VEGF expression by ganglion cells in central retina before formation of the foveal depression in monkey retina: evidence of developmental hypoxia.

In macaque monkeys the foveal depression forms between fetal day (Fd) 105 and birth (Fd 172 of gestation). Before this, the incipient fovea is identified by a photoreceptor layer comprising cones almost exclusively, a multilayered ganglion cell layer (GCL), and a "domed" profile. Vessels are absent from the central retina until late in development, leading to the suggestion that the GCL in the incipient fovea may be transitorily hypoxic. Vascular endothelial growth factor (VEGF), expressed by both glial and neuronal cells and mediated by the hypoxia-inducible transcription factor (HIF)-1, is the principal factor involved in blood vessel growth in the retina. We examined VEGF expression in macaque retinas between Fd 85 and 4 months postnatal. Digoxygenin-labeled riboprobes were generated from a partial-length human cDNA polymerase chain reaction fragment, detected using fluorescence confocal microscopy, and quantified using Scion Image. High levels of VEGF mRNA were detected in astrocytes associated with developing vessels. We also detected strong expression of VEGF mRNA in the GCL at the incipient fovea prior to Fd 105, with peak labeling in the incipient fovea that declined with distance in nasal and temporal directions. By Fd 152 peak labeling was in two bands associated with development of the inner nuclear layer (INL) capillary plexus: in the inner INL where Müller and amacrine cell somas are located, and in the outer INL where horizontal cells are found. The findings suggest that at the incipient fovea the GCL is hypoxic, supporting the hypothesis that the adaptive significance of the fovea centralis is in ensuring adequate oxygen supply to neuronal elements initially located within the avascular region.

Impaired hyaloidal circulation function and uncoordinated ocular growth patterns in experimental retinopathy of prematurity.

PURPOSE: To test the hypotheses that, in the newborn rat model of retinopathy of prematurity (ROP), the hyaloidal circulation is functionally impaired and its development is not well coordinated with that of other ocular structures. METHODS: The functional response of the hyaloidal circulation to a carbogen inhalation challenge was noninvasively evaluated using magnetic resonance imaging (MRI) in day 12 rats raised under either variable oxygen conditions (experimental ROP, n = 8) or room air (control, n = 8). A similar MRI examination was performed in separate experiments using either day 18 newborn control rats (n = 3) or adult rats (n = 9). For each experiment, the hyaloidal circulation perfusion response to carbogen, the functional spatial extent of the hyaloidal circulation in vitreous, and the volumes of vitreous and lens were estimated from MRI enhancement maps. RESULTS: The hyaloidal perfusion response to carbogen breathing in the newborn rats decreased as follows: control day 12 > experimental day 12 > control day 18; no measurable hyaloidal function was found in the adult rat. Regression analysis indicated a relatively poorer superior-inferior correlation in the temporal response to carbogen inhalation for the experimental animals than in the control newborn rats. The vitreous volume decreased in control rats as expected (adult rat > day 18 > day 12). Good agreement was found between the MRI-determined adult rat vitreous volume (56 +/- 2 microliters) and that of previous reports. Functional hyaloidal volumes during carbogen breathing were not significantly different (P > 0.05) between day 18, day 12 control, and experimental newborn rats. The ratio of this functional hyaloidal circulation extent volume to vitreous volume was significantly different (P < 0.05) between these groups. Covariance analysis revealed a relatively less coordinated development between the functional hyaloidal volume and the vitreous volume in experimental animals than in age-matched control animals, whereas there was coordinated evolution of the hyaloidal circulation and the lens in all the animals. CONCLUSIONS: Carbogen-enhanced MRI appears to be a powerful new and noninvasive approach for assessing the functionality of the hyaloidal circulation (that is, its ability to respond to a carbogen challenge) and quantitatively comparing the functional hyaloidal extent to other ocular volumes in the same eye during development and during the disease process. Evidence is presented here for the first time that supports the authors' hypotheses that the function of the hyaloidal circulation in experimental ROP is impaired and that the growth of ocular components are less coordinated.

[Vitreous hemorrhage associated with persistent hyaloid artery. Apropos of a case]. / Hémorragie intravitréenne associée à une persistance de l'artère hyaloïde. A propos d'un cas.

We report a case of vitreous haemorrhage from a persistent hyaloid artery that occurred to a 50 year-old patient. The case report is followed by a review of the embryologic development and a physiopathologic discussion about the origin of vitreous haemorrhage. The authors emphasize the distinction between persistent hyaloid artery and persistent hyperplastic primary vitreous.

Association between cilioretinal arteries and juxtapapillary scars.

We examined the relationship of cilioretinal arteries (CRAs) to juxtapapillary chorioretinal scars, along with the developmental significance of the latter in relation to CRA formation. Both eyes of 360 patients were studied. Sixty-eight (18.9%) of these patients had a CRA in at least one eye, 13 of these 68 (19.1%) had one in both. The CRAs were distributed equally between right and left eyes. Two hundred eight patients (57.8%) had a scar in at least one eye; 157 of these (75.5%) had one in both. The presence of a CRA was significantly associated with the presence of a scar. Since both are common developmental variations, this correlation points to a common embryologic formation mechanism.

Hemi-central retinal vein occulsion. Pathogenesis, clinical features, and natural history.

A two-trunked central retinal vein (CRV) in the anterior part of the optic nerve may persist as a congenital abnormality in a certain proportion of humans. One of the two trunks, like the CRV, may get occulded in the optic nerve to produce hemi-CRV occulsion (hemi-CRVO). It is shown that hemi-CRVO is a distinct entity, clincially and pathogenetically closely related to CRVO, and unrelated to branch retinal vein occlusion because of fundamental differences between the two. Hemi-CRVO clinically presents as either venous stasis retinopathy (VSR) or as hemorrhagic retinopathy (HR), usually involving one half of the retina, although ocassionally it may involve one third to two thirds of the retina. The clinical features of VSR and HR caused by hemi-CRVO are identical to those caused by CRVO. The primary object of this article is to identity hemi-CRVO, a not uncommon condition, and to describe its main clinical features.