Abstract
Purpose: :
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of transcription factors activated by a number of ligands, including naturally occurring fatty acids, NSAIDS, and prostaglandins. There are three PPAR subtypes: α, β/Δ, and γ. Evidence suggests that PPAR β/Δ may regulate VEGF-induced pathological angiogenesis. Therefore, we investigated the effect of pharmacologic activation and inhibition of PPAR β/Δ on human retinal microvascular endothelial cell (HRMEC) behavior and in a model of oxygen-induced retinopathy (OIR).
Methods: :
The angiogenic behavior of HRMEC was assessed by proliferation and tubulogenesis assays in the presence of increasing doses of the PPAR β/Δ agonist GW0742 or antagonist GSK0660. An OIR rat model was used to assess the effect of PPAR β/Δ on development of neovascularization (NV). GW0742 and GSK0660 were administered locally by intravitreal injection and systemically by oral gavage and intraperitoneal injection, respectively.
Results: :
Activation of PPAR β/Δ by GW0742 had no effect on HRMEC proliferation, but resulted in a 118% increase (p < 0.0001) of tube formation at the highest concentration (1.0 μM). Inhibition by GSK0660 caused a dose-dependent decrease in serum-induced proliferation (39%; p = 0.0034) and tube formation (40%; p = 0.0039) at the highest concentration (1.0μM). Intravitreal injection of GW0742 at the highest concentration (500nM) increased NV by 52% (p = 0.044) and GSK0660 at the highest concentration (500nM) inhibited NV by 45% (p = 0.015). A similar but more pronounced effect was observed with systemic injections; 10mg/kg GW0742 caused a 190% increase (p = 0.024) and 1mg/kg GSK0660 caused a 67% reduction (p = 0.0003) of NV.
Conclusions: :
Activation of PPAR β/Δ significantly increases pathological NV in OIR, while antagonism significantly inhibits NV. This suggests that this transcription factor may constitute a rational target for chemotherapeutic intervention in ocular angiogenesis.
Keywords: retinal neovascularization • transcription factors • retinopathy of prematurity