title: Oxidative stress induces loss of pericyte coverage and vascular instability in PGC-1α-deficient mice.
abstract: 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.
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Arturo Duperier 4, Room 1.3.2, 28029-, Madrid, Spain.|Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolas Cabrera 1, 28049-, Madrid, Spain.
authors.forename: Nieves
authors.initials: N
authors.lastname: García-Quintans
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Arturo Duperier 4, Room 1.3.2, 28029-, Madrid, Spain.|Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Melchor Fernández Almagro 3, 28029-, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez-Ramos
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Arturo Duperier 4, Room 1.3.2, 28029-, Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Prieto
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Melchor Fernández Almagro 3, 28029-, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Tierrez
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Melchor Fernández Almagro 3, 28029-, Madrid, Spain.
authors.forename: Elvira
authors.initials: E
authors.lastname: Arza
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Melchor Fernández Almagro 3, 28029-, Madrid, Spain.|Fundación para la Investigación Biomédida del Hospital Universitario La Princesa, Diego de León 62, 28006-, Madrid, Spain.
authors.forename: Arantzazu
authors.initials: A
authors.lastname: Alfranca
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Melchor Fernández Almagro 3, 28029-, Madrid, Spain.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Redondo
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Arturo Duperier 4, Room 1.3.2, 28029-, Madrid, Spain. mpmonsalve@iib.uam.es.
authors.forename: María
authors.initials: M
authors.lastname: Monsalve
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010100:Oxygen; D010477:Perfusion; D020286:Pericytes / Q000378:metabolism* / Q000473:pathology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000172:deficiency* / Q000378:metabolism*; D012160:Retina / Q000473:pathology; D012164:Retinal Diseases / Q000378:metabolism / Q000473:pathology
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D010100:Oxygen
keywords: Angiogenesis; PGC-1α; ROS; Retinopathy; Vascular stability