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Anand Giddabasappa, Jeetendra R. Eswaraka, Christina M. Barrett, Matthew N. Bauler, Zhongzhi Wu, Muralimohan Yepuru, Duane D. Miller, James T. Dalton; β-LGND2, an ERβ Selective Agonist, Inhibits Pathologic Retinal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2012;53(8):5066-5075. doi: 10.1167/iovs.12-9627.
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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).
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.
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.
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.
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