| Autor: |
Sheibani N; Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., Song YS; Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., Farnoodian M; Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., Inampudi S; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., Hanna B; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., Wang S; Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., Darjatmoko SR; Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., Sorenson CM; McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. |
| Abstrakt: |
In the aging population, choroidal vessels grow through the Bruch's membrane, resulting in a loss of central vision due to choroidal neovascularization (CNV). During active neovascularization, CNV is associated with inappropriate levels of apoptosis in multiple cell types, including choroidal endothelial cells (ChECs). Bim is a pro-apoptotic member of the Bcl-2 family. It is essential for cell apoptosis due to exposure to drugs such as dexamethasone or decreased pro-survival factors, including vascular endothelial growth factor (VEGF). To better elucidate the cell autonomous contribution of Bim expression in the integrity and neovascularization of the choroidal vasculature, we isolated ChECs from wild-type and Bim-deficient (Bim -/- ) mice. ChECs lacking Bim expression demonstrated increased expression of VEGF, osteopontin, and the inflammatory cytokines Rantes/Ccl5 and IL6. Bim -/- ChECs were more proliferative and demonstrated an increased capacity to undergo capillary morphogenesis. Anti-VEGF had a diminished capacity to disrupt capillary morphogenesis in Bim -/- ChECs. In vivo, utilizing the mouse laser photocoagulation model, anti-VEGF treatment mitigated CNV in wild-type but not Bim -/- mice. We also tested other modalities that are thought to not require the intrinsic death pathway for their function and showed that propranolol, anti-CTGF, and the TSP1-mimetic peptide ABT898 mitigated CNV in mice lacking Bim expression to varying degrees. Thus, in ChECs, Bim expression could impact the effectiveness of treatment modalities that require the intrinsic death pathway to mitigate CNV. |
