Regulation of endothelial dynamics by PGC-1α relies on ROS control of VEGF-A signaling
| Autor: | Yolanda Olmos, Nieves García-Quintans, Alfonso Luque, Cristina Sánchez-Ramos, María Monsalve, Ignacio Prieto, Elvira Arza |
|---|---|
| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Comunidad de Madrid |
| Rok vydání: | 2016 |
| Předmět: |
Vascular Endothelial Growth Factor A
0301 basic medicine Mitochondrial ROS Angiogenesis PGC-1α Mitochondrion Biochemistry VEGF-A Antioxidants Focal adhesion Extracellular matrix Mice 03 medical and health sciences 0302 clinical medicine Antigens CD Physiology (medical) Vascular endothelium Organometallic Compounds Animals Humans chemistry.chemical_classification Reactive oxygen species Neovascularization Pathologic Endothelial Cells Cell migration Cadherins Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Salicylates Extracellular Matrix Mitochondria Cell biology Oxidative Stress 030104 developmental biology Gene Expression Regulation chemistry Oxidative stress Signal transduction 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 0891-5849 |
| Popis: | 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. [Aims]: This study aims to investigate the role of ROS on the regulation by PGC-1α of angiogenesis. [Methods and 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. This work was supported by grants from the Spanish ‘‘Ministerio de Economía y Competitividad’’ [Grant no. SAF2009-07599 & SAF2012-37693 to M.M and CSD 2007-00020 to M.M.]; and the ‘‘Comunidad Autónoma de Madrid’’ [Grant no. S2010/BMD-2361 to M.M.]. |
| Databáze: | OpenAIRE |
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