Hypoxia inducible vascular endothelial growth factor (VEGF) plays a major role in initiation and regulation of retinal neovascularization, which is the leading cause of severe vision loss and irreversible blindness in developed countries. Src family kinases (SFKs) are involved in a broad spectrum of cellular events. However, their roles in VEGF-mediated pathological retinal angiogenesis are completely unknown. My investigation showed that in vitro SFKs were essential for hypoxia-induced VEGF expression in retinal glial Müller cells, a major source of VEGF secretion during the pathogenesis of retinopathy, and for VEGF signaling in retinal microvascular endothelial cells (RMECs). However, neither process required phosphorylation of the SFK activation loop Tyr416. In addition, in RMECs, coexpressed SFK members Src, Fyn and Yes each displayed distinct properties in the regulation of VEGF-mediated cell events. All three kinases were required for VEGF mitogenic signaling. VEGF-induced cell migration was significantly increased in Fyn-deficient cells and decreased in Yes-deficient cells. Interference of Fyn, but not Src or Yes, impaired VEGF-induced tube formation in RMECs. In vivo, in a rat model of oxygen-induced retinopathy (OIR), I found that a significant increase of SFK Tyr416 phosphorylation was specifically associated with pathological retinal angiogenesis, but not with physiological intraretinal vascularizaion. Müller cells were the source of the elevated phospho-SFK Tyr416 signal. VEGF expression was also highly increased in these OIR retinas. Intravitreous injection of a selective SFK inhibitor (PP2) significantly reduced retinopathy. These findings indicate that aberrant SFK signaling may be an important factor in the pathogenesis of retinal neovascularization. Increased SFK activity or individual SFK member(s) are potential targets for therapeutic intervention in VEGF-mediated retinopathy.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03292005-163659 |
| Date | 06 April 2005 |
| Creators | Werdich, Xiang Qi |
| Contributors | David M. Miller, Ann Richmond, Jin Chen, Franco M. Recchia, John S. Penn |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03292005-163659/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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