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J.L. Wilkinson-Berka, S. Sarlos, B. Rizkalla, C.J. Moravski, Z. Cao, M.E. Cooper; Retinal Angiogenesis Is Mediated by an Interaction Between the Angiotensin Type 2 receptor, VEGF and Angiopoietin in a Rat Model of Retinopathy of Prematurity . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2885.
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Purpose: There is evidence that angiotensin II, vascular endothelial growth factor (VEGF), angiopoietins and their cognate receptors participate in retinal angiogenesis. Most of the blood pressure and cell growth effects of angiotensin II are elicted by the angiotensin type 1 (AT1) receptor. The role of the angiotensin type 2 (AT2) receptor is less well defined, although it is highly expressed in developing tissues where it may modulate cell growth and differentiation. We investigated whether AT2 receptor antagonism (AT2-RB) reduces retinal angiogenesis and alters the expression of VEGF/VEGF-R2 and angiopoietin-Tie2. Methods: Retinopathy of prematurity (ROP) was induced in Sprague Dawley (SD) rats by exposure to 80% oxygen from postnatal (P) days 0-11, followed by 7 days in room air. ROP shams were in room air from P0-18. A group of ROP rats received the AT2-RB, PD123319, by miniosmotic pump (5mg/kg/day) from P11-18 (angiogenesis period). The abundance of the AT1 and AT2 receptors was evaluated in SD retina at P days 1,7,14,21 and 90. Results: Evaluation of the retinal status of the AT2 receptor indicated that this receptor, as assessed by real-time PCR, immunohistochemistry and in vitro autoradiography, was present in the retina, was more abundant than the AT1 receptor in the neonatal retina and was increased in the ROP model. AT2-RB with PD123319 reduced retinal new vessel formation. Gene expression for VEGF and VEGF-R2 revealed an increase in the ROP model which was localised to blood vessels, ganglion cells and the inner nuclear layer and were decreased by PD123319. Angiopoietin2 and Tie2, but not angiopoietin1 mRNA were increased with ROP, and angiopoietin2 was reduced with PD123319. Conclusions: The present study has identified a potential retinoprotective role for AT2 receptor inhibition possibly mediated via interactions with VEGF and angiopoietin dependent pathways. These findings extend the evidence for a pivotal role of the renin-angiotensin system in retinal disorders.
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