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P. Kozulin, R. Natoli, K. M. Bumsted O'Brien, M. C. Madigan, J. M. Provis; The Expression of Anti-Angiogenic Factors in Fetal Primate Retina and Their Possible Role in Vascular Patterning. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4015.
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© ARVO (1962-2015); The Authors (2016-present)
Development of the retinal vasculature is mediated by vascular endothelial growth factor (VEGF). Vascular development in the macular region of primate retina is 'retarded', no large retinal vessels form there, and the foveal region is never vascularized. We identified by microarray analysis 3 anti-angiogenic factors differentially expressed in the macula of human fetal retina at 19-20 weeks' gestation. Here we examine further the expression and localization of these factors.
Quantitative PCR (QPCR) was used to verify differential gene expression in RNA from human fetal retinas. Proteins and mRNA expression were localized by immunohistochemistry and in situ hybridization in fetal human and macaque retinas.
QPCR confirmed the microarray findings showing higher levels of expression of brain natriuretic peptide (BNP) and pigment epithelium derived factor (PEDF) in central retina, and lower levels of collagen type 42 (COL4A2). BNP mRNA was detected in ganglion and Müller cells and in the vascular endothelium of large retinal vessels. BNP protein localized to Müller cell processes, particularly in the inner retina, vascular endothelial cells and ganglion cells. PEDF mRNA was detected in the ganglion cell layer (GCL) and RPE. High-to-low, centre-to-periphery expression gradients of both BNP and PEDF mRNAs were detected in the GCL of fetal macaque retinas. COL4A2 protein was localized to blood vessel walls in vascularized peripheral retina. No COL4A2 was observed in the developing macula.
Elevated expression of PEDF and BNP in the developing macula may antagonize VEGF during development, retard vessel formation and help to define the foveal avascular area. Down-regulation of COL4A2 in the macula corresponds with its presence on mature vessels in peripheral retina. These results may assist in the development of new therapeutic strategies to inhibit neovascularization of the macular region.
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