Oxidative stress induces loss of pericyte coverage and vascular instability in PGC-1α-deficient mice

Peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1 alpha) is a regulator of mitochondrial oxidative metabolism and reactive oxygen species (ROS) homeostasis that is known to be inactivated in diabetic subjects. This study aimed to investigate the contribution of PGC-1 alpha inactivation to the development of oxygen-induced retinopathy. We analyzed retinal vascular development in PGC-1 alpha(-/-) mice. Retinal vasculature of PGC-1 alpha(-/-) mice showed reduced pericyte coverage, a de-structured vascular plexus, and low perfusion. Exposure of PGC-1 alpha(-/-) mice to hyperoxia during retinal vascular development exacerbated these vascular abnormalities, with extensive retinal hemorrhaging and highly unstructured areas as compared with wild-type mice. Structural analysis demonstrated a reduction in membrane-bound VE-cadherin, which was suggestive of defective intercellular junctions. Interestingly, PGC-1 alpha(-/-) retinas showed a constitutive activation of the VEGF-A signaling pathway. This phenotype could be partially reversed by antioxidant administration, indicating that elevated production of ROS in the absence of PGC-1 alpha could be a relevant factor in the alteration of the VEGF-A signaling pathway. Collectively, our findings suggest that PGC-1 alpha control of ROS homeostasis plays an important role in the regulation of de novo angiogenesis and is required for vascular stability.