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K.M. Nishiguchi, H. Kaneko, M. Nakamura, H. Terasaki; VEGF Promotes the Regeneration of Photoreceptors by Enhancing the Proliferation of the Retinal Progenitor Cells via VEGFR2 in Murine Retinal Degeneration . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1067.
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© ARVO (1962-2015); The Authors (2016-present)
Recent evidence suggests that the VEGF, a known potent angiogenic factor, also plays a role in the neurogenesis. In this study, we analyzed the role of VEGF and its receptors in the retinal neurogenesis using mice with retinal degeneration (rd1 mice).
We studied the level of the VEGF from developing retinas of the wild–type mice and the rd1 mice with ELISA. The retinal explants from rd1 mice cultured in media with variable concentration of VEGF, anti–VEGFR1 neutralizing antibody, or a potent inhibitor of VEGFR2 kinase, SU1498, were histologically analyzed. VEGF was injected in the vitreous of post–natal day (P) 6 rd1 mice in one eye and PBS in the other. The eyes were enucleated at various ages, frozened, sectioned, and these sections were immunohistochemically evaluated using the following antibodies or staining agents; anti–BrdU antibody, TUNEL kit, anti–rhodopsin antibody, anti–LM cone antibody, anti–recoverin antibody, anti–VEGFR1 antibody, anti–VEGFR2 antibody, and DAPI.
BrdU–positive cells from P6 rd1 mouse retina expressed VEGFR2 but not VEGFR1; these cells later developed into rod and cone photoreceptors indicating they are retinal progenitor cells. The expression of VEGF was significantly reduced in rd1 retina compared with wild–type retina. Administration of VEGF into the culture medium with retinal explants from the rd1 mice resulted in a dose dependent increase of the BrdU–positive cells (P<0.01) but had no effect on the number of TUNEL–positive apoptotic cells. This neurogenic effect of VEGF on the BrdU–positive cells was inhibited dose dependently by the administration of VEGFR2 inhibitor, SU1498 (P<0.01), while VEGFR1–neutralizing antibody had no effect. Intravitreal injection of VEGF, compared with PBS injection, in P6 rd1 mouse, resulted in an increased number of BrdU–positive cells (labeled during P9–12) at the peripheral retina (8.0 ± 3.4 versus 5.4 ± 1.9, P<0.05) and the non–pigemented epithelium of the ciliary body (22.4 ± 14.9 versus 13.2 ± 4.7, P<0.05) in P30 retina. However, there was no detectable rescue effect on the total number of rods or cones in the outer nuclear layer.
VEGF stimulates the proliferation of the BrdU–positive retinal progenitor cells via VEGFR2 but not VEGFR1 in vitro in rd1 mouse. Intravitreal injection of VEGF promoted the regeneration of the retinal photoreceptors at the peripheral retina in vivo. Restoring the expression of VEGF in the degenerating retina may slow the progression of the disease by promoting the regeneration of the photoreceptors.
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