Thiazolidinediones reduce pathological neovascularization in ischemic retina via an adiponectin-dependent mechanism

Abstract

BACKGROUND-: The insulin-sensitizing agents referred to as thiazolidinediones (TZDs) possess antiatherogenic and anti-inflammatory actions that contribute to protection against diabetic macrovascular complications. However, little is known about the effects of TZDs on retinal microvessel disorders. OBJECTIVE-: To investigate whether TZDs modulate retinal vessel formation in a mouse model of oxygen-induced retinopathy. METHODS AND RESULTS-: Neonatal mice were subjected to ischemia-induced retinopathy to produce pathological neovascular tuft formation. Pioglitazone, 10 mg/kg per day, rosiglitazone, 10 mg/kg per day, or vehicle was given by gavage once a day from postnatal day 7 to postnatal day 17. Systemic treatment of wild-type (WT) mice with TZDs led to a significant decrease in pathological retinal neovascularization during ischemia compared with vehicle treatment, which was accompanied by increased plasma levels of the fat-derived hormone adiponectin (APN). In contrast to WT mice, TZDs had no effects on ischemia-induced pathological retinal vessel formation in APN-knockout (KO) mice. Pioglitazone reduced tumor necrosis factor (TNF) α expression in ischemic retina in WT mice but not in APN-KO mice. Furthermore, pioglitazone increased plasma APN levels in TNF-α-KO mice but did not affect ischemia-induced pathological retinal neovascularization in this strain. CONCLUSION-: These data show that TZDs attenuate pathological retinal microvessel formation through APN-mediated modulation of TNF-α production. © 2010 American Heart Association, Inc.