Purchase this article with an account.
J. S. Penn, G. W. McCollum, S. E. Yanni, M. S. Assadian, R. Yang; PPAR-beta in Retinal Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2958.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Peroxisome proliferator-activated receptors (PPARs) are nuclear membrane receptors that exist as three subtypes - a, b and g. PPARs are activated by a number of ligands, including naturally occurring fatty acids, NSAIDs, and prostaglandins. Of the three PPAR subtypes, PPAR-b appears to play a role in cell proliferation. The purpose of this study was to determine whether PPAR-b is pro-angiogenic in the retina.
In vitro, retinal Müller cells were subjected to normoxia or hypoxia for 24 hrs. Retinal microvascular endothelial cells (RMEC) were treated with and without VEGF for 24 hrs. Microarray analysis of PPAR-b-related genes was performed. Müller cells were treated with a PPAR-b inhibitor, sulindac sulfide (SS), or with siRNA directed against PPAR-b, and hypoxia-induced VEGF production was measured. RMEC were treated with SS, or with PPAR-b-directed siRNA, and VEGF-induced proliferation and tube formation were measured. RMEC were treated with cPGI, a stable analog of PGI2 (a known ligand for PPAR-b), and PPAR-b activation was measured. In vivo, rats were subjected to OIR, treated with SS, and neovascular (NV) area was measured.
Hypoxic Müller cells and VEGF-treated RMEC demonstrated a significant increase (p = 0.01) in PPAR-b expression. Expression of adipose differentiation-related protein (ADRP), a protein exclusively regulated by PPAR-b, demonstrated a 6-fold increase in hypoxic Müller cells. SS and PPAR-b-directed siRNA resulted in dose-dependent inhibition of hypoxia-induced VEGF production in Müller cells and VEGF-induced proliferation (p= 0.005) and tube formation in RMEC. RMEC treated with cPGI demonstrated a 3.5-fold increase in PPAR-b activation, measured by ADRP expression. In OIR rats, SS demonstrated a dose-dependent reduction in NV area that reached 50%.
In vitro, inhibiting PPAR-b led to both an inhibition of Müller cell and RMEC angiogenic cell behaviors, suggesting that it may play multiple roles in regulating angiogenesis. In vivo, PPAR-b inhibition reduced pathological retinal NV. These findings suggest that PPAR-b may constitute a novel and rational target for chemotherapeutic intervention in ocular angiogenesis.
This PDF is available to Subscribers Only