Nonvascular role for vascular endothelial growth factor (VEGF): VEGFR‐1 and VEGFR‐2 activity is critical for neural retinal development

ABSTRACT The purpose of this study was to evaluate the function of extravascular vascular endothelial growth factor (VEGF) receptors in developing neural retina. VEGF is routinely described as a vascular endothelial cell‐specific mitogen, and VEGF receptor 1 (VEGFR‐1) and VEGF receptor 2 (VEGFR‐2) are described as endothelial cell specific, but there is evidence that these VEGF receptors are found outside the vasculature in neural tissue. The developing eye presents a unique opportunity to examine the function of VEGF in neural tissue alone. The peripheral retina is normally avascular at birth and becomes vascularized over the first 2 wk after birth. We localized VEGFR‐1 and ‐2 mRNA and protein to extravascular neuronal tissue during early retinal development. Avascular cornea also expresses these receptors. Inhibition of VEGFR‐1 and ‐2 in vivo with a specific small‐molecule tyrosine kinase antagonist, SU5416, inhibits development of the nonvascularized immature retina, resulting in cell loss in the inner retina, including the inner nuclear layer containing Muller cells and the ganglion cell layer containing astrocytes. Isolated retinal Muller cells express both VEGF receptors. VEGF stimulation activates MAPK, which is abrogated with inhibition of the receptors. We conclude that VEGFR‐ 1 and ‐2 are necessary for normal neural retinal development independent of vascular development.