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. J. Comp. Neurol. 462:42–54, 2003. © 2003 Wiley‐Liss, Inc.

Wholemounts of human fetal retinas were labeled with antibodies to Ki67 or proliferating cell nuclear antigen, to map the distribution of proliferating cells in the developing primary vasculature and neural retina. Double labeling was used to determine the relative proportions of endothelial cells (CD34), astrocytes (glial fibrillary acidic protein - GFAP) and microglia (major histocompatability complex class II) associated with the developing vessels. The differentiated region of neural retina (cold spot) was 3.5 mm(2)at 15 weeks gestation (WG), centred on the incipient fovea, and increased in size with age to 80.5 mm(2)by 23-24 WG. Ki67 immunoreactive cells were distributed throughout the developing vasculature at all ages. The mean density of dividing cells in the neural retina increased with gestational age from 146 mm(-2)at 15 WG, to 624 mm(-2)at 23-24 WG. By 20 WG proliferation in the vasculature overlapped the margins of the cold spot, which was almost completely vascularized by 23-24 WG, except for a narrow strip on the horizontal meridian, which included the incipient fovea. Counts of CD34/Ki67 immunoreactive cells indicated that 15-52% of proliferations in the developing vasculature at 18 WG are endothelial cells. In contrast, in the fellow retina 65-85% cells were Ki67/GFAP immunoreactive, indicating proliferation of astrocytes in situ. No dividing microglia were observed. The findings suggest that large numbers of proliferating astrocytes accompany the developing vessels as they migrate across the primate retina.