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J.S. Penn, D. Hicks, G.W. McCollum, V.S. Rajaratnam, X. Qi, J. Chen; A Soluble Ephrin Receptor Blocks Angiogenic Responses in Retinal Endothelial Cells and Inhibits Neovascularization in a Rat ROP Model . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2882.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: The Eph family of receptor tyrosine kinases (RTK) and their ligands, known as ephrins, play a crucial role in vascular development during embryogenesis, but their function in adult angiogenesis remains unclear. Our purpose is to determine the effect of blocking ephrin activity on VEGF-induced angiogenic responses of endothelial cells and on retinal neovascularization (NV) in a rodent model of retinopathy of prematurity (ROP). Methods: Bovine retinal microvascular endothelial cells (BRMEC) were plated at appropriate densities, starved in serum-free medium for 24 hours, and then treated for 24 hours with 25ng/ml VEGF in the presence or absence of a soluble EphA2-fc receptor at concentrations ranging from 0.5 - 20 µg/ml. From birth, rats were exposed to variable oxygen (range, 10 - 50 %) for 14 days, removed to room air for 6 days and sacrificed for assessment of retinal vascular area and NV. EphA2-fc was administered by intravitreal injection at the time of removal from exposure (14/0) or two days later (14/2). Results: BRMEC migration and tube formation, but not proliferation, were inhibited in a dose-dependent manner by EphA2-fc. The optimal dose, 10µg/ml, resulted in 40% reduction of cell migration (p < 0.01) and 60% reduction in tube formation (p < 0.01). Retinal NV in ROP rats was also inhibited in a dose-dependent fashion when soluble receptor was injected at 14/2 (48%; p = 0.043), but not 14/0 (37%; p = 0.241). Conclusions: The ephrins have joined VEGF isoforms and angiopoietins as endothelial cell RTK ligands with the capacity to modulate angiogenesis. Although the ephrins are the least well characterized of these three groups of ligands, the therapeutic potential of targeting them is supported by these data and by previous in vivo studies of pancreatic islet cell carcinoma and metastatic mammary adenocarcinoma. This strategy warrants further investigation in the context of ocular angiogenesis.
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