ZFIN ID: ZDB-PUB-100322-11
ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish
Ren, B., Deng, Y., Mukhopadhyay, A., Lanahan, A.A., Zhuang, Z.W., Moodie, K.L., Mulligan-Kehoe, M.J., Byzova, T.V., Peterson, R.T., and Simons, M.
Date: 2010
Source: J. Clin. Invest.   120(4): 1217-1228 (Journal)
Registered Authors: Peterson, Randall
Keywords: none
MeSH Terms:
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Arteries/growth & development*
  • Carrier Proteins/physiology
  • Male
  • Mice
  • Mitogen-Activated Protein Kinase 1/physiology*
  • Mitogen-Activated Protein Kinase 3/physiology*
  • Morphogenesis*
  • Neovascularization, Physiologic
  • Neuropeptides/physiology
  • Phosphatidylinositol 3-Kinases/physiology
  • Proto-Oncogene Proteins c-akt/physiology*
  • Signal Transduction/physiology
  • Vascular Endothelial Growth Factor A/pharmacology
  • Vascular Endothelial Growth Factor Receptor-2/physiology
  • Zebrafish
PubMed: 20237411 Full text @ J. Clin. Invest.
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.