β-LGND2, an ERβ selective agonist, inhibits pathologic retinal neovascularization

Anand Giddabasappa, Jeetendra R. Eswaraka, Christina M. Barrett, Matthew N. Bauler, Zhongzhi Wu, Muralimohan Yepuru, Duane Miller, James T. Dalton

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5066-5075
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume53
Issue number8
DOIs
StatePublished - Jul 1 2012

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Pathologic Neovascularization
Retinal Neovascularization
Oxygen
Intercellular Signaling Peptides and Proteins
Cell Death
Endothelial Cells
Cell Migration Assays
Protein Array Analysis
Hyperoxia
Eye Diseases
Angiogenesis Inducing Agents
Diabetic Retinopathy
Lectins
Vascular Endothelial Growth Factor A
Transcriptional Activation
Cell Movement
Blood Vessels
Retina
Histology
Proteins

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Giddabasappa, A., Eswaraka, J. R., Barrett, C. M., Bauler, M. N., Wu, Z., Yepuru, M., ... Dalton, J. T. (2012). β-LGND2, an ERβ selective agonist, inhibits pathologic retinal neovascularization. Investigative Ophthalmology and Visual Science, 53(8), 5066-5075. https://doi.org/10.1167/iovs.12-9627

β-LGND2, an ERβ selective agonist, inhibits pathologic retinal neovascularization. / Giddabasappa, Anand; Eswaraka, Jeetendra R.; Barrett, Christina M.; Bauler, Matthew N.; Wu, Zhongzhi; Yepuru, Muralimohan; Miller, Duane; Dalton, James T.

In: Investigative Ophthalmology and Visual Science, Vol. 53, No. 8, 01.07.2012, p. 5066-5075.

Research output: Contribution to journalArticle

Giddabasappa, A, Eswaraka, JR, Barrett, CM, Bauler, MN, Wu, Z, Yepuru, M, Miller, D & Dalton, JT 2012, 'β-LGND2, an ERβ selective agonist, inhibits pathologic retinal neovascularization', Investigative Ophthalmology and Visual Science, vol. 53, no. 8, pp. 5066-5075. https://doi.org/10.1167/iovs.12-9627
Giddabasappa, Anand ; Eswaraka, Jeetendra R. ; Barrett, Christina M. ; Bauler, Matthew N. ; Wu, Zhongzhi ; Yepuru, Muralimohan ; Miller, Duane ; Dalton, James T. / β-LGND2, an ERβ selective agonist, inhibits pathologic retinal neovascularization. In: Investigative Ophthalmology and Visual Science. 2012 ; Vol. 53, No. 8. pp. 5066-5075.
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AU - Bauler, Matthew N.

AU - Wu, Zhongzhi

AU - Yepuru, Muralimohan

AU - Miller, Duane

AU - Dalton, James T.

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N2 - 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.

AB - 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.

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