ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish.
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.
Department of Cell Biology, Cleveland Clinic Foundation, Ohio, USA.
Bin
B
Ren
Yong
Y
Deng
Arpita
A
Mukhopadhyay
Anthony A
AA
Lanahan
Zhen W
ZW
Zhuang
Karen L
KL
Moodie
Mary Jo
MJ
Mulligan-Kehoe
Tatiana V
TV
Byzova
Randall T
RT
Peterson
Michael
M
Simons
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001158:Arteries / Q000254:growth & development*; D002352:Carrier Proteins / Q000502:physiology; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D009024:Morphogenesis; D018919:Neovascularization, Physiologic; D009479:Neuropeptides / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D029961:Zebrafish Proteins; C511793:GIPC1 protein, zebrafish; C115271:Gipc1 protein, mouse; C514862:Akt1 protein, mouse