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Sara R Savage, Laura L Davia, John S Penn; Inhibition of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) reduces choroidal angiogenesis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3449.
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Age-related macular degeneration (AMD) is one of the leading causes of blindness in the United States. AMD is characterized by abnormal proliferation of the choroidal vasculature into the sub-retinal space, hypothetically in response to VEGF produced by hypoxic retinal pigmented epithelium (RPE). Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a transcription factor that regulates energy homeostasis, lipid catabolism, and glucose metabolism. Our lab recently reported a potent inhibitory effect of PPARβ/δ antagonism on pre-retinal neovascularization. In the present study, we sought to determine if PPARβ/δ plays a similar role in sub-retinal neovascularization of the sort occurring in AMD.
Primary mouse RPE and ARPE-19 were treated with increasing concentrations of the PPARβ/δ antagonist GSK0660 in hypoxia. Secreted VEGF was analyzed by ELISA. The angiogenic behavior of human choroidal endothelial cells (HCEC) was assessed by proliferation and tube formation assays in the presence of GSK0660. Vascular sprouting from mouse choroid explants was also analyzed in the presence of GSK0660.
Treatment with GSK0660 reduced hypoxia-induced VEGF production by both primary mouse RPE and ARPE-19 (p<0.025). Proliferation of HCEC stimulated by both VEGF and 2% FBS medium was reduced by GSK0660 (p<0.0001), as was tube formation stimulated by VEGF (p=0.0007). GSK0660 reduced the area of angiogenic sprouting of choroid explants by 30% (p=0.025).
PPARβ/δ plays a role both upstream and downstream in choroidal angiogenesis. Inhibition of PPARβ/δ reduces VEGF secretion from RPE while also inhibiting the angiogenic response of HCEC to VEGF. Based on these findings, PPARβ/δ may constitute a rational therapeutic target for treatment of neovascular AMD.
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