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J. Ambati, M. Nozaki, E. Sakurai, J.Z. Baffi, A. Takeda, B.J. Raisler, B.K. Ambati; VEGF–A Suppresses Choroidal Neovascularization via HO–1 . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1831.
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© ARVO (1962-2015); The Authors (2016-present)
We recently described a novel anti–angiogenic action of VEGF–A following injury in the laser–induced choroidal neovascularization (CNV) model. We sought to determine whether heme oxygenase (HO)–1, a potent anti–inflammatory heat shock protein, mediated this neovascular suppression by VEGF–A.
CNV was induced by laser injury in C57BL/6J and HO–1–/– mice, and volumes measured 7 days later by confocal evaluation of Griffonia simplicifolia Isolectin B4 staining of RPE–choroid flatmounts. VEGF–A and hemin (HO–1 inducer) were injected into the vitreous immediately after injury. The HO–1 antagonist zinc protoporphyrin IX (ZnPP) and control copper protoporphyrin IX (CuPP) were injected intravenously after injury. Flow cytometry was used to quantify choroidal macrophage infiltration and the cell cycle state of choroidal endothelial cells (CECs) in vivo. Proliferation in HO–1–/– and HO–1+/+ endothelial cells was assessed. HO–1, p21, and cyclin D1 expression in RPE/choroid were studied by western blotting.
VEGF–A augmented laser injury induced HO–1, and suppressed both macrophage infiltration and CNV development. ZnPP but not CuPP negated, while hemin promoted, the anti–inflammatory and anti–angiogenic effects of VEGF–A. Experiments in HO–1–/– mice confirmed these results. VEGF–A induced G0/G1 cell cycle arrest of CECs via HO–1 induction of p21 and suppression of cyclin D1. Experiments in HO–1–/– cells confirmed these results.
VEGF–A–induced suppression of angiogenesis following injury is mediated via HO–1 mediated anti–inflammatory and anti–proliferative effects on CECs, providing new molecular targets for intervention in neovascular AMD.
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