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

• Published in: Angiogenesis (London) 2016-04, Vol.19 (2), p.217-228
• 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
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Blood Vessels - metabolism; Blood Vessels - pathology; Cancer Research; Cardiology; Cell Biology; Mice, Inbred C57BL; Oncology; Ophthalmology; Original Paper; Oxidative Stress; Oxygen; Perfusion; Pericytes - metabolism; Pericytes - pathology; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - deficiency; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Retina - pathology; Retinal Diseases - metabolism; Retinal Diseases - pathology
• ISSN: 0969-6970; 1573-7209
• DOI: 10.1007/s10456-016-9502-0

Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) 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-1α inactivation to the development of oxygen-induced retinopathy. We analyzed retinal vascular development in PGC-1α −/− mice. Retinal vasculature of PGC-1α −/− mice showed reduced pericyte coverage, a de-structured vascular plexus, and low perfusion. Exposure of PGC-1α −/− 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-1α −/− 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-1α could be a relevant factor in the alteration of the VEGF-A signaling pathway. Collectively, our findings suggest that PGC-1α control of ROS homeostasis plays an important role in the regulation of de novo angiogenesis and is required for vascular stability.