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

• Published in: Angiogenesis (London) 2016-06, Vol.19 (2), p.217
• Main Authors: García-quintans, Nieves, Sánchez-ramos, Cristina, Prieto, Ignacio, Tierrez, Alberto, Arza, Elvira, Alfranca, Arantzazu, Redondo, Juan Miguel, Monsalve, María
• Format: Article
• Language: English
• ISSN: 0969-6970; 1573-7209
• DOI: 10.1007/s10456-016-9502-0

Peroxisome proliferator-activated receptor γ 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]^sup -/-^ mice. Retinal vasculature of PGC-1[alpha]^sup -/-^ mice showed reduced pericyte coverage, a de-structured vascular plexus, and low perfusion. Exposure of PGC-1[alpha]^sup -/-^ 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]^sup -/-^ 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.