title: Regulation of endothelial dynamics by PGC-1α relies on ROS control of VEGF-A signaling.
abstract: Peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α) is a regulator of mitochondrial metabolism and reactive oxygen species (ROS) that is known to play a relevant role in angiogenesis.
  
  
  OBJECTIVE
  This study aims to investigate the role of ROS on the regulation by PGC-1α of angiogenesis.
  
  
  RESULTS
  We found that endothelial cells (ECs) from mice deleted for PGC-1α display attenuated adhesion to the extracellular matrix, together with slower and reversible spreading. Structural analysis demonstrates unstable formation of focal adhesions, defective cytoskeleton reorganization in response to cellular matrix adhesion, cell migration and cell-cell adhesion. Confluent cultures showed also a reduction of membrane bound VE-cadherin, suggesting defective inter-cellular junction formation. Functional consequences included impaired directional migration, and enhanced tip phenotype in aortic explants sprouting assays. At the molecular level, PGC-1α-deleted ECs exhibit a constitutive activation of the vascular endothelial growth factor-A (VEGF-A) signaling pathway and a defective response to VEGF-A. All these alterations are partially reversed by administration of the antioxidant EUK-189. The contribution of mitochondrial ROS and NOX activation was confirmed using a mitochondrial targeted antioxidant (MitoTEMPO) and a NOX inhibitor (VAS-2870). These results indicate that elevated production of ROS in the absence of PGC-1α is a key factor in the alteration of the VEGF-A signaling pathway and the capacity of endothelial cells to form stable interactions with other endothelial cells and with the extracellular matrix. Our findings show that PGC-1α control of ROS homeostasis plays an important role in the control of endothelial response to VEGF-A.
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Arturo Duperier 4, 28029 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, 28029 Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Prieto
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez-Ramos
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Luque
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.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Olmos
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain. Electronic address: mpmonsalve@iib.uam.es.
authors.forename: María
authors.initials: M
authors.lastname: Monsalve
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics*; D009942:Organometallic Compounds / Q000008:administration & dosage; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000096:biosynthesis* / Q000235:genetics; D012459:Salicylates / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D000975:Antioxidants; D015820:Cadherins; D009942:Organometallic Compounds; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012459:Salicylates; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5; C436526:EUK-189; C467484:VEGFA protein, human
keywords: Mitochondria; Oxidative stress; PGC-1α; VEGF-A; Vascular endothelium