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Originally published In Press as doi:10.1167/iovs.08-2461 on August 29, 2008
 (Investigative Ophthalmology and Visual Science. 2009;50:311-321.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.08-2461
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Role of Cell and Matrix-Bound VEGF Isoforms in Lens Development

Magali Saint-Geniez,1,2 Tomoki Kurihara,1 and Patricia A. D'Amore1,2,3

1From the Schepens Eye Research Institute and the 2Departments of Ophthalmology and 3Pathology, Harvard Medical School, Boston, Massachusetts.

PURPOSE. To determine the role of vascular endothelial growth factor (VEGF) in embryonic eye development and lens differentiation.

METHODS. Expression of components of the VEGF signaling pathway during lens development and in adults was characterized by β-galactosidase staining of VEGF-LacZ mice, immunohistochemistry, and real-time (q) PCR. Embryonic eyes from wild-type mice and VEGF120/120 mice were analyzed by light microscopy and immunohistochemistry. VEGF function during lens development was analyzed using eye explants treated with VEGF-neutralizing antibody. Direct function of VEGF was demonstrated on the human lens epithelial cell line, HLE-B3.

RESULTS. Embryonic lens epithelium and posterior lens fibers expressed VEGF and VEGFR2. qPCR revealed VEGF164 as the major isoform in embryonic lens. Transgenic mice expressing only VEGF120 (VEGF120/120 mice) showed major defects in eye development, including microphthalmia, failed lens differentiation, and hyperplastic hyaloid vessels. The lens displayed abnormal cell patterning and differentiation associated with altered c-Maf, Prox1, and p57 expression pattern in the anterior epithelium. The number of proliferating epithelial cells was drastically reduced in VEGF120/120 lenses. Altered MIP26 cellular localization and reduced E-cadherin expression in the lens epithelium were observed. VEGF-neutralization led to reduced fiber elongation of eye explants. Exogenous VEGF increased survival and proliferation of HLE-B3 cell in a dose-dependent manner.

CONCLUSIONS. Abnormalities in ocular development in VEGF120/120 mice suggest a role for VEGF not only in the formation of ocular vascular beds but also in the differentiation of the lens itself.






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