Abstract
Purpose: :
Epidemiological studies suggest that estrogen deficiency in post-menopausal women increases the risk for developing age-related macular degeneration (AMD). Pathological neovascularization, vascular leakage, retinal pigment epithelium and photoreceptor cell death are hallmark features of Wet-AMD. The goal of this study was to evaluate the in vitro and in vivo anti-angiogenic effects of GTx-878, a selective estrogen receptor modulator (SERM) using endothelial cell cultures and the mouse model for oxygen-induced retinopathy (OIR).
Methods: :
HRMVEC cells were exposed to hypoxia and hyperoxia and the cell death was measured using cell death ELISA kit. In vitro angiogenesis was evaluated by tube formation assay using the HRMVEC cell line. OIR in C57BL/6 mice was used as an animal model to study pathological neovascularization and the effects of GTx-878. Flat mounts of retinas were stained with isolectin B4 and the amount of angiogenesis was quantitated. Gene expression studies were performed by Q-PCR.
Results: :
Tube formation assays showed that GTx-878 inhibited the formation of endothelial tubular structures. Exposure of HRMVECs to hypoxic and hyperoxic stress resulted in apoptosis. Pretreatment of the cells with GTx-878 abrogated the cell death and preserved cellular morphology. Treatment of OIR mice with GTx-878 reduced the number of neovascular tufts in the extra retinal zone, compared to that of animals treated with vehicle alone. Interestingly the drug treated animals showed significant amount of normal blood vessel maturation similar to that of the normoxia controls.
Conclusions: :
GTx-878 inhibited pathological neovascularization in the retina and may represent a new treatment for wet AMD.
Keywords: age-related macular degeneration • neovascularization • hypoxia