Thiazolidinediones Reduce Pathological Neovascularization in Ischemic Retina Via an Adiponectin-Dependent Mechanism

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)alpha expression in ischemic retina in WT mice but not in APN-KO mice. Furthermore, pioglitazone increased plasma APN levels in TNF-alpha-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-alpha production. (Arterioscler Thromb Vasc Biol. 2010;30:46-53.)