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- Title
ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish.
- Authors
Bin Ren; Yong Deng; Mukhopadhyay, Arpita; Lanahan, Anthony A.; Zhuang, Zhen W.; Moodie, Karen L.; Mulligan-Kehoe, Mary Jo; Byzova, Tatiana V.; Peterson, Randall T.; Simons, Michael; Ren, Bin; Deng, Yong
- 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
MORPHOGENESIS; CROSSTALK; MICE; ZEBRA danio; ATHEROSCLEROSIS; VASCULAR diseases; CELL receptors; ANIMALS; ARTERIES; CARRIER proteins; CELLULAR signal transduction; FISHES; NEOVASCULARIZATION; NEUROPEPTIDES; PHOSPHOTRANSFERASES; TRANSFERASES; VASCULAR endothelial growth factors; CELL physiology
- Publication
Journal of Clinical Investigation, 2010, Vol 120, Issue 4, p1217
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI39837