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ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2010 Apr; Vol. 120 (4), pp. 1217-28. Date of Electronic Publication: 2010 Mar 08. - Publication Year :
- 2010
-
Abstract
- Arterial morphogenesis is an important and poorly understood process. In particular, the signaling events controlling arterial formation have not been established. We evaluated whether alterations in the balance between ERK1/2 and PI3K signaling pathways could stimulate arterial formation in the setting of defective arterial morphogenesis in mice and zebrafish. Increased ERK1/2 activity in mouse ECs with reduced VEGF responsiveness was achieved in vitro and in vivo by downregulating PI3K activity, suppressing Akt1 but not Akt2 expression, or introducing a constitutively active ERK1/2 construct. Such restoration of ERK1/2 activation was sufficient to restore impaired arterial development and branching morphogenesis in synectin-deficient mice and synectin-knockdown zebrafish. The same approach effectively stimulated arterial growth in adult mice, restoring arteriogenesis in mice lacking synectin and in atherosclerotic mice lacking both LDL-R and ApoB48. We therefore conclude that PI3K-ERK1/2 crosstalk plays a key role in the regulation of arterial growth and that the augmentation of ERK signaling via suppression of the PI3K signaling pathway can effectively stimulate arteriogenesis.
- Subjects :
- Adaptor Proteins, Signal Transducing
Animals
Carrier Proteins physiology
Male
Mice
Neovascularization, Physiologic
Neuropeptides physiology
Phosphatidylinositol 3-Kinases physiology
Signal Transduction physiology
Vascular Endothelial Growth Factor A pharmacology
Vascular Endothelial Growth Factor Receptor-2 physiology
Zebrafish
Zebrafish Proteins
Arteries growth & development
Mitogen-Activated Protein Kinase 1 physiology
Mitogen-Activated Protein Kinase 3 physiology
Morphogenesis
Proto-Oncogene Proteins c-akt physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 120
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 20237411
- Full Text :
- https://doi.org/10.1172/JCI39837