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Cellular context–mediated Akt dynamics regulates MAP kinase signaling thresholds during angiogenesis

The formation of new blood vessels by sprouting angiogenesis is tightly regulated by contextual cues that affect angiogeneic growth factor signaling. Both constitutive activation and loss of Akt kinase activity in endothelial cells impair angiogenesis, suggesting that Akt dynamics mediates contextua...

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Detalles Bibliográficos
Autores principales: Hellesøy, Monica, Lorens, James B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501366/
https://www.ncbi.nlm.nih.gov/pubmed/26023089
http://dx.doi.org/10.1091/mbc.E14-09-1378
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author Hellesøy, Monica
Lorens, James B.
author_facet Hellesøy, Monica
Lorens, James B.
author_sort Hellesøy, Monica
collection PubMed
description The formation of new blood vessels by sprouting angiogenesis is tightly regulated by contextual cues that affect angiogeneic growth factor signaling. Both constitutive activation and loss of Akt kinase activity in endothelial cells impair angiogenesis, suggesting that Akt dynamics mediates contextual microenvironmental regulation. We explored the temporal regulation of Akt in endothelial cells during formation of capillary-like networks induced by cell–cell contact with vascular smooth muscle cells (vSMCs) and vSMC-associated VEGF. Expression of constitutively active Akt1 strongly inhibited network formation, whereas hemiphosphorylated Akt1 epi-alleles with reduced kinase activity had an intermediate inhibitory effect. Conversely, inhibition of Akt signaling did not affect endothelial cell migration or morphogenesis in vSMC cocultures that generate capillary-like structures. We found that endothelial Akt activity is transiently blocked by proteasomal degradation in the presence of SMCs during the initial phase of capillary-like structure formation. Suppressed Akt activity corresponded to the increased endothelial MAP kinase signaling that was required for angiogenic endothelial morphogenesis. These results reveal a regulatory principle by which cellular context regulates Akt protein dynamics, which determines MAP kinase signaling thresholds necessary drive a morphogenetic program during angiogenesis.
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spelling pubmed-45013662015-09-30 Cellular context–mediated Akt dynamics regulates MAP kinase signaling thresholds during angiogenesis Hellesøy, Monica Lorens, James B. Mol Biol Cell Articles The formation of new blood vessels by sprouting angiogenesis is tightly regulated by contextual cues that affect angiogeneic growth factor signaling. Both constitutive activation and loss of Akt kinase activity in endothelial cells impair angiogenesis, suggesting that Akt dynamics mediates contextual microenvironmental regulation. We explored the temporal regulation of Akt in endothelial cells during formation of capillary-like networks induced by cell–cell contact with vascular smooth muscle cells (vSMCs) and vSMC-associated VEGF. Expression of constitutively active Akt1 strongly inhibited network formation, whereas hemiphosphorylated Akt1 epi-alleles with reduced kinase activity had an intermediate inhibitory effect. Conversely, inhibition of Akt signaling did not affect endothelial cell migration or morphogenesis in vSMC cocultures that generate capillary-like structures. We found that endothelial Akt activity is transiently blocked by proteasomal degradation in the presence of SMCs during the initial phase of capillary-like structure formation. Suppressed Akt activity corresponded to the increased endothelial MAP kinase signaling that was required for angiogenic endothelial morphogenesis. These results reveal a regulatory principle by which cellular context regulates Akt protein dynamics, which determines MAP kinase signaling thresholds necessary drive a morphogenetic program during angiogenesis. The American Society for Cell Biology 2015-07-15 /pmc/articles/PMC4501366/ /pubmed/26023089 http://dx.doi.org/10.1091/mbc.E14-09-1378 Text en © 2015 Hellesøy and Lorens. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Hellesøy, Monica
Lorens, James B.
Cellular context–mediated Akt dynamics regulates MAP kinase signaling thresholds during angiogenesis
title Cellular context–mediated Akt dynamics regulates MAP kinase signaling thresholds during angiogenesis
title_full Cellular context–mediated Akt dynamics regulates MAP kinase signaling thresholds during angiogenesis
title_fullStr Cellular context–mediated Akt dynamics regulates MAP kinase signaling thresholds during angiogenesis
title_full_unstemmed Cellular context–mediated Akt dynamics regulates MAP kinase signaling thresholds during angiogenesis
title_short Cellular context–mediated Akt dynamics regulates MAP kinase signaling thresholds during angiogenesis
title_sort cellular context–mediated akt dynamics regulates map kinase signaling thresholds during angiogenesis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501366/
https://www.ncbi.nlm.nih.gov/pubmed/26023089
http://dx.doi.org/10.1091/mbc.E14-09-1378
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