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

Area of Science:

• Ophthalmology
• Endocrinology
• Molecular Biology

Background:

• Aberrant angiogenesis is a key factor in several blinding ocular diseases.
• Estrogen receptor beta (ERβ) plays a role in regulating vascularization.
• Targeting ERβ offers a potential therapeutic strategy for neovascular eye conditions.

Purpose of the Study:

• To investigate the anti-angiogenic effects of the ERβ-selective agonist, β-LGND2.
• To evaluate β-LGND2 in vitro using human retinal microvascular endothelial cells (HRMVECs).
• To assess β-LGND2 in vivo using a mouse model of oxygen-induced retinopathy (OIR).

Main Methods:

• Assessed β-LGND2 selectivity via binding and transactivation assays.
• Quantified neovascularization in OIR mice using histology and isolectin B4 staining.
• Evaluated gene and protein expression of angiogenic factors (VEGF, HIF1α) using Q-PCR, protein arrays, and Western blotting.
• Assessed in vitro angiogenesis, cell death, proliferation, and migration in HRMVECs.

Main Results:

• β-LGND2 treatment significantly reduced neovascular tufts in OIR mice.
• β-LGND2 inhibited hypoxia/hyperoxia-induced HRMVEC cell death and tube formation via an ERβ-specific mechanism.
• β-LGND2 did not significantly inhibit growth factor-induced HRMVEC proliferation or migration.
• β-LGND2 treatment lowered levels of pro-angiogenic factors VEGF and HIF1α in OIR mice.

Conclusions:

• β-LGND2 demonstrates potent in vitro and in vivo anti-angiogenic effects in the retina through an ERβ-specific pathway.
• β-LGND2, a non-steroidal ERβ agonist, is a potential therapeutic agent for ocular diseases involving aberrant angiogenesis.
• Therapeutic applications include retinopathy of prematurity (ROP), wet age-related macular degeneration (wet-AMD), and diabetic retinopathy.