PURPOSE: Ephrin ligands and their Eph receptors are key regulators of endothelial cell (EC) proliferation, migration, adhesion, and repulsion during mammalian vascular development. The hypothesis was that these molecules also play a role in pathologic neovascularization (NV) in the mouse model of oxygen-induced retinopathy. METHODS: C57BL/6 mice at postnatal day (P)7 were exposed to 75% oxygen (O(2)) for 5 days (until P12) and allowed to recover in room air to induce retinal NV. Retinas from unexposed and hyperoxia-exposed mice between P7 to P24 were analyzed specifically for EphrinB2 and EphB4 transcript expression by RT-PCR. Phospho-Eph (p-Eph) receptor was evaluated during active EC proliferation at P15 and P17 by immunohistology. Some hyperoxia-exposed mice had one eye injected intravitreally with 150 ng/1.5 microL of soluble EphrinB2/Fc or EphB4/Fc chimeras during transition from high O(2) to room air (P12) and injected again on P14. Contralateral eyes were injected with human IgG as the control. Preretinal nuclei and retinal blood vessels were quantified at peak disease (P17). RESULTS: EphrinB2 mRNA was constitutively expressed in the developing retina and was unchanged by hyperoxia. In contrast, EphB4 mRNA expression was modulated during normal retinal development and was altered by hyperoxia. Furthermore, p-Eph was detected in developing preretinal tufts, thus implying that Ephrin/Eph signaling system is active in this experimental model. Intravitreal injection of soluble versions of these molecules significantly reduced pathologic neovascularization. The number of preretinal nuclei in hyperoxia-treated mice was reduced by 66% (P < 0.05) in EphrinB2-injected eyes, whereas EphB4 treatment yielded a 69% reduction (P < 0.05), compared with control injections. Intraretinal vessel development was not altered by the injections. CONCLUSIONS: These results support the hypothesis that endogenous EphrinB2 and EphB4 are regulators of retinal NV during oxygen-induced retinopathy and may be useful targets for therapeutic intervention.
PURPOSE: Ephrin ligands and their Eph receptors are key regulators of endothelial cell (EC) proliferation, migration, adhesion, and repulsion during mammalian vascular development. The hypothesis was that these molecules also play a role in pathologic neovascularization (NV) in the mouse model of oxygen-induced retinopathy. METHODS: C57BL/6 mice at postnatal day (P)7 were exposed to 75% oxygen (O(2)) for 5 days (until P12) and allowed to recover in room air to induce retinal NV. Retinas from unexposed and hyperoxia-exposed mice between P7 to P24 were analyzed specifically for EphrinB2 and EphB4 transcript expression by RT-PCR. Phospho-Eph (p-Eph) receptor was evaluated during active EC proliferation at P15 and P17 by immunohistology. Some hyperoxia-exposed mice had one eye injected intravitreally with 150 ng/1.5 microL of soluble EphrinB2/Fc or EphB4/Fc chimeras during transition from high O(2) to room air (P12) and injected again on P14. Contralateral eyes were injected with human IgG as the control. Preretinal nuclei and retinal blood vessels were quantified at peak disease (P17). RESULTS:EphrinB2 mRNA was constitutively expressed in the developing retina and was unchanged by hyperoxia. In contrast, EphB4 mRNA expression was modulated during normal retinal development and was altered by hyperoxia. Furthermore, p-Eph was detected in developing preretinal tufts, thus implying that Ephrin/Eph signaling system is active in this experimental model. Intravitreal injection of soluble versions of these molecules significantly reduced pathologic neovascularization. The number of preretinal nuclei in hyperoxia-treated mice was reduced by 66% (P < 0.05) in EphrinB2-injected eyes, whereas EphB4 treatment yielded a 69% reduction (P < 0.05), compared with control injections. Intraretinal vessel development was not altered by the injections. CONCLUSIONS: These results support the hypothesis that endogenous EphrinB2 and EphB4 are regulators of retinal NV during oxygen-induced retinopathy and may be useful targets for therapeutic intervention.
Authors: Sunila Pradeep; Jie Huang; Edna M Mora; Alpa M Nick; Min Soon Cho; Sherry Y Wu; Kyunghee Noh; Chad V Pecot; Rajesha Rupaimoole; Martin A Stein; Stephan Brock; Yunfei Wen; Chiyi Xiong; Kshipra Gharpure; Jean M Hansen; Archana S Nagaraja; Rebecca A Previs; Pablo Vivas-Mejia; Hee Dong Han; Wei Hu; Lingegowda S Mangala; Behrouz Zand; Loren J Stagg; John E Ladbury; Bulent Ozpolat; S Neslihan Alpay; Masato Nishimura; Rebecca L Stone; Koji Matsuo; Guillermo N Armaiz-Peña; Heather J Dalton; Christopher Danes; Blake Goodman; Cristian Rodriguez-Aguayo; Carola Kruger; Armin Schneider; Shyon Haghpeykar; Padmavathi Jaladurgam; Mien-Chie Hung; Robert L Coleman; Jinsong Liu; Chun Li; Diana Urbauer; Gabriel Lopez-Berestein; David B Jackson; Anil K Sood Journal: Cancer Cell Date: 2015-10-17 Impact factor: 31.743
Authors: Terri A Dimaio; Shoujian Wang; Qiong Huang; Elizabeth A Scheef; Christine M Sorenson; Nader Sheibani Journal: Dev Biol Date: 2008-01-22 Impact factor: 3.582
Authors: Peter Kozulin; Riccardo Natoli; Michele C Madigan; Keely M Bumsted O'Brien; Jan M Provis Journal: Mol Vis Date: 2009-12-09 Impact factor: 2.367