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E. Im, A. Kazlauskas; Regulating Angiogenesis at the Level of PI–4,5–P2 . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4182.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Phosphoinositides are central to many intracellular signaling pathways that direct cellular and biological processes such as angiogenesis. For instance, phosphoinositol–4,5–bisphosphate (PI–4,5–P2) is the substrate for both phospholipase Cγ (PLCγ) and phosphoinositide 3 kinase (PI3K), enzymes that initiate ubiquituous intracellular signaling cascades. The pro–angiogenic agent vascular endothelial growth factor (VEGF) activates both PLCγ and PI3K, which could result in a competition for PI–4,5–P2. The purpose of this paper was to test the hypothesis that angiogenesis is regulated by an intrinsic rivalry between PI3K and PLCγ for PI–4,5–P2. Methods: We used tube formation by primary bovine retinal endothelial cells (BRECs) as an in vitro angiogenesis assay. These cells secrete PDGF, and by expressing the platelet–derived growth factor ß receptor (PDGFR) in them, we established a system in which tube formation was dependent on PDGFR signaling. We also generated cells expressing a panel of PDGFR signaling mutants, which permitted us to assess the relationship between PI3K and PLCγ. Akt phosphorylation level was measured by Western blotting. Results: Consistent with the work of other groups using more traditional approaches, we found that PI3K was necessary for both the formation and stability of tubes. Receptors capable of activating both PI3K and PLCγ were able to form tube, however the tubes were not stable. Tube regression correlated with a reduced output of the PI3K signaling pathway, and could be reversed by the administration of synthetic PI–4,5–P2. Conclusions: Our results suggest that PI3K and PLCγ compete for PI–4,5–P2, and that this may be an underlying cause of instability of newly formed or pathological vessels. Our ongoing studies will test the prediction that PLCγ–mediated antagonism of PI3K occurs at the level of PI–4,5–P2 and contributes to hyaloid vessel regression in vivo.
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