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Neovascularization is associated with mTOR activation in O 2 ‐induced retinopathy
Author(s) -
Shenberger Jeffrey S,
Zhang Lianqin,
Kimball Scot,
Jefferson Leonard S
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1091.6
Subject(s) - pi3k/akt/mtor pathway , p70 s6 kinase 1 , phosphorylation , protein kinase b , retinopathy of prematurity , ribosomal protein s6 , neovascularization , retinal , vascular endothelial growth factor , andrology , medicine , cancer research , chemistry , endocrinology , biology , angiogenesis , microbiology and biotechnology , signal transduction , vegf receptors , ophthalmology , pregnancy , genetics , gestational age
Retinopathy of prematurity (ROP) and the oxygen‐induced retinopathy (OIR) mouse model are characterized by increased neovascularization (NV). Induction of NV correlates with an increase in vascular growth factors including both VEGF and FGF2. Because mTOR is known to regulate growth factor expression in other forms of vasculopathy, we studied mTOR signaling in the OIR model of ROP to shed light on mTOR's role in NV. We studied newborn BALB/cJ mice exposed to 75% O 2 from postnatal (P) day 7–12 to induce vascular regression followed by the return to room air through P17 to stimulate NV. We found that O 2 induced vascular regression at P12 without altering the phosphorylation of the upstream mTOR activators Akt (Thr 308 ) and TSC2 (Thr 1461 ), the mTOR substrates 4E‐BP1 (Ser 65 ) and p70S6K (Thr 389 ), or the p70S6K substrate ribosomal S6 protein (Thr 235/236 ). Pre‐retinal nuclei were not seen in control mice at any time, while OIR mice displayed increased pre‐retinal nuclei indicative of NV at both P15 and P17. Phosphorylation of Akt and TSC2 were initially depressed at P13 in the NV phase but returned to the level of control pups thereafter. The phosphorylation of S6K1 and 4E‐BP1 increased during NV at P14‐16 while the phosphorylation of S6rp increased during NV at P15‐16. These findings demonstrate that induction of NV in OIR is preceded by activation of mTOR potentially leading to increased vascular growth factor expression.