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M. Saint-Geniez, P. A. D'Amore; Role of the VEGF Isoforms During Eye Development and in the Maintenance of the RPE-Choriocapillaris in the Adult. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1226.
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© ARVO (1962-2015); The Authors (2016-present)
VEGF in mice is produced as three alternatively spliced isoforms (VEGF120, VEGF164 and VEGF188) that differ in their binding affinity for heparan sulfate proteoglycan. Transgenic mice expressing single isoforms display organ-specific abnormalities associated with defective angiogenesis. Here we investigated the role of the VEGF120 and VEGF188 in the eye during early development and in the adult.
Eye development was studied at E13.5 and E18.5 by histology and IHC in mice expressing only VEGF120 or VEGF188. The role of VEGF during lens development was further analyzed using lens explants treated with VEGF inhibitors. The RPE-choroid in adult VEGF188 mice was examined by TEM.
VEFG120 mice displayed significant abnormalities during eye development, with reduced eye size and failed lens development. While the primitive choroid appeared normal, hyaloid vessels were dilated. Surprisingly, the lens showed the most remarkable defects with abnormal lens cell patterning and differentiation. IHC and RT-PCR of developing lens revealed that both lens epithelium and posterior lens fiber cells express VEGF and VEGFR2. Culture of lens explants in the presence of sFlt demonstrated the role of VEGF signaling in lens. While eye formation in VEGF188 mice appeared normal, TEM showed age-dependent abnormalities in the RPE/choroids complex, with changes characterized by loss of the choriocapillaris and severe enlargment of the choroidal vessels associated with marked disruption of the Bruchâ€TMs membrane layers beginning around seven months. Aging of the VEGF188 mice was also associated with vacuolization, detachment and hyperpigmentation of RPE.
Abnormalities in ocular development in mice expressing only VEGF120 suggest a role for VEGF not only in the formation of ocular vascular beds but also reveal a new function for VEGF in the differentiation of the lens itself. The absence of eye defects in early ocular development of VEGF188 mice suggest that membrane-bound VEGF is sufficient for proper eye development. A role for diffusible VEGF in maintenance of the underlying choriocapillaris is indicated by the development of severe RPE-choriocapillaris defects in aged VEGF188 mice. We speculate that formation of Bruchâ€TMs membrane presents an obstacle that renders the non-diffusible VEGF188 unable to reach the VEGFR2 expressing choriocapillaris, leading to abnormalities that recapitulate some of the clinical features of dry AMD.
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