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X.Q. Werdich, J.S. Penn; Src Family Kinases, New Therapeutic Targets for Intervention of VEGF–Mediated Retinopathy . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1426.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Vascular endothelial growth factor (VEGF)–mediated retinopathy is strongly influenced by events both upstream and downstream from VEGF receptor activation. Src family kinases (SFKs), which are involved in a broad spectrum of cellular events including VEGF induction and signaling, may play important roles in the pathogenesis of retinopathy. Methods: A rat model of oxygen–induced retinopathy was used for in vivo studies. Primary rat Müller cells and bovine or human retinal microvascular endothelial cells (RMECs) were used for in vitro studies. Expression of individual SFK members, Src, Fyn or Yes, was knocked down by RNA interference. Results: In vivo, SFKs were specifically activated in Müller cells of the oxygen–injured retina, in parallel with substantially increased retinal VEGF levels. Phospho–SFK Tyr416, which is directly correlated with the enzyme’s kinase activity, was also seen in the normal retinal vascular bed and in preretinal vascular tufts. Efficient inhibition of retinopathy by intravitreous injection of a selective SFK inhibitor, PP2, confirmed the involvement of SFKs in the abnormal retinal angiogenesis. In vitro, SFK baseline kinase activity, but not activation through phosphorylation of Tyr416, was required for VEGF induction by hypoxia in Müller cells and VEGF signaling in endothelial cells. In RMECs, SFKs were rapidly recruited to VEGFR2 upon VEGF stimulation. Src, Fyn and Yes were all required for the VEGF mitogenic signal, but may not fully participate in the apoptotic pathway marked by DNA fragmentation. The three enzymes differentially regulated VEGF–induced cell migration. RMECs deficient in Fyn alone or Src, Fyn and Yes together showed significantly impaired VEGF–mediated tube formation. Conclusions: Activation of SFKs through phosphorylation of Tyr416 is specifically involved in the pathogenesis of retinal neovascularization, but not the physiological events of VEGF induction by hypoxia in Müller cells and VEGF signaling in RMECs. Closely related Src, Fyn and Yes possess unique functions in VEGF signaling in endothelial cells. Selective intervention of member(s) reduces possible complications that would likely result from broad spectrum inhibition of SFKs.
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