β-LGND2, an ERβ selective agonist, inhibits pathologic retinal neovascularization.
| Autor: | Giddabasappa A; Preclinical Research and Development, GTx Inc., 3 N. Dunlap Street. Memphis, TN 38163, USA., Eswaraka JR, Barrett CM, Bauler MN, Wu Z, Yepuru M, Miller DD, Dalton JT |
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| Jazyk: | angličtina |
| Zdroj: | Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2012 Jul 31; Vol. 53 (8), pp. 5066-75. Date of Electronic Publication: 2012 Jul 31. |
| DOI: | 10.1167/iovs.12-9627 |
| Abstrakt: | Purpose: The goal of our study was to evaluate the in vitro and in vivo anti-angiogenic effects of ERβ selective agonist, β-LGND2, using human retinal microvascular endothelial cell (HRMVEC) cultures and a mouse model for oxygen-induced retinopathy (OIR). Methods: The selectivity of β-LGND2 was determined using binding and transactivation assays. The effects of β-LGND2 on pathologic neovascularization were evaluated in OIR mice by histology and retinal mounts stained with isolectin B4 to quantify aberrant angiogenesis. Gene expression and protein levels were evaluated using Q-PCR, angiogenesis protein array, and Western blotting. A cell death detection ELISA kit was used to evaluate HRMVECs following hypoxic and hyperoxic conditions. In vitro angiogenesis was evaluated by growth factor-induced proliferation, tube formation, and cell migration assays. Results: β-LGND2-treated OIR mice had a reduced number of neovascular tufts compared to vehicle-treated animals and a significant amount of normal blood vessel maturation similar to normoxia controls. β-LGND2 inhibited in vitro hypoxia- or hyperoxia-induced cell death and the formation of endothelial tubular structures in an ERβ-specific mechanism. However, β-LGND2 did not inhibit significantly growth factor-induced HRMVEC proliferation and migration. Gene and protein studies revealed that OIR mice treated with β-LGND2 had lower levels of pro-angiogenic factors, like VEGF and HIF1α. Conclusions: β-LGND2 inhibited in vitro and in vivo pathologic neovascularization in the retina in an ERβ-specific mechanism. These results show that β-LGND2, a non-steroidal ERβ selective agonist, could be a useful therapeutic for ocular diseases involving aberrant angiogenesis, like ROP, wet-AMD, and diabetic retinopathy. |
| Databáze: | MEDLINE |
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