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Title

Regulation of endothelial dynamics by PGC-1α relies on ROS control of VEGF-A signaling

AuthorsGarcía-Quintans, Nieves CSIC; Prieto, Ignacio; Sánchez-Ramos, Cristina; Luque, Alfonso; Arza, Elvira; Olmos, Yolanda; Monsalve, María CSIC ORCID
KeywordsVascular endothelium
VEGF-A
Oxidative stress
Mitochondria
PGC-1α
Issue Date2016
PublisherElsevier
CitationFree Radical Biology and Medicine 93: 41-51 (2016)
AbstractPeroxisome 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.
Publisher version (URL)https://doi.org/10.1016/j.freeradbiomed.2016.01.021
URIhttp://hdl.handle.net/10261/150935
DOIhttp://dx.doi.org/10.1016/j.freeradbiomed.2016.01.021
Identifiersdoi: 10.1016/j.freeradbiomed.2016.01.021
e-issn: 1873-4596
issn: 0891-5849
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