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Regulation of endothelial function and angiogenesis by PGC-1α relies on ROS control of vascular stability

AuthorsGarcía-Quintans, Nieves ; Sánchez-Ramos, Cristina; Tierrez, Albert; Olmos, Yolanda ; Luque, Alfonso; Arza, Elvira; Alfranca, Arántzazu; Redondo, Juan Miguel ; Monsalve, María
Issue Date2015
CitationXXXVIII Congreso de la SEBBM (2015)
Abstract[Background]: Peroxisome proliferator activated receptor g co-activator 1a (PGC-1a) is a regulator of mitochondrial oxidative metabolism and reactive oxygen species (ROS) homeostasis that has been show to play a relevant role in angiogenesis. This study aims to investigate the role of ROS homeostasis on the regulation by PGC-1a of angiogenesis. [Methods and results]: We found that endothelial cells (ECs) from mice deleted for PGC-1a display attenuated adhesion to the extracellular matrix, together with slower spreading, reduced formation of cellular junctions, a disorganized cytoskeleton and random motility, and a enhanced tip phenotype. Additionally, PGC-1a-deleted ECs exhibit an altered response to vascular endothelial growth factor-A (VEGF-A). In vivo, deletion of PGC-1a results in reduced pericyte coverage, a de-structured vascular plexus, and low perfusion. Exposure of PGC-1a-/- mice to hyperoxia during retinal vascular development exacerbates these vascular abnormalities. Mice show extensive retinal hemorrhaging and highly unstructured areas compared with wild-type mice. Structural analysis demonstrates a reduction of membrane bound VE-cadherin, suggesting defective inter-cellular junctions. Interestingly, PGC-1a-/- retinas and ECs show a constitutive activation of the VEGF-A signaling pathway and a poor response to VEGF-A stimulation. This phenotype is partially reversed both in vitro and in vivo by antioxidant administration, indicating that elevated production of mitochondrial ROS in the absence of PGC-1a is a key factor in the alteration of the VEGF-A signaling pathway. [Conclusions]: In summary, our fi ndings indicate that PGC-1a control of ROS homeostasis plays an important role in the control of de novo angiogenesis, and is required for vascular stability.
DescriptionResumen del póster presentado al XXXVIII Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Valencia del 7 al 10 de septiembre de 2015.
Appears in Collections:(IIBM) Comunicaciones congresos
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