ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish. J Clin Invest 2010 Apr;120(4):1217-28
Date
03/20/2010Pubmed ID
20237411Pubmed Central ID
PMC2846043DOI
10.1172/JCI39837Scopus ID
2-s2.0-77951160785 (requires institutional sign-in at Scopus site) 129 CitationsAbstract
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.
Author List
Ren B, Deng Y, Mukhopadhyay A, Lanahan AA, Zhuang ZW, Moodie KL, Mulligan-Kehoe MJ, Byzova TV, Peterson RT, Simons MMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAnimals
Arteries
Carrier Proteins
Male
Mice
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Morphogenesis
Neovascularization, Physiologic
Neuropeptides
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Signal Transduction
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
Zebrafish
Zebrafish Proteins
