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ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish
Bin Ren1, Yong Deng, Arpita Mukhopadhyay
1Department of Cell Biology, Cleveland Clinic Foundation, Ohio, USA.
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.
Insights
Altering the balance between ERK1/2 and PI3K signaling pathways can stimulate arterial formation and growth. Suppressing PI3K activity enhances ERK1/2 signaling, promoting arteriogenesis in both developmental and adult models.
Area of Science:
- Vascular biology
- Molecular signaling
- Developmental biology
Background:
- Arterial morphogenesis is crucial but poorly understood.
- Signaling pathways controlling arterial formation remain unclear.
Purpose of the Study:
- To investigate if modulating ERK1/2 and PI3K signaling impacts arterial formation.
- To determine if enhancing ERK1/2 activity can restore defective arterial development.
Main Methods:
- Manipulated PI3K and ERK1/2 signaling in mouse endothelial cells (ECs) and in vivo models (mice, zebrafish).
- Utilized genetic knockdown (synectin), pharmacological inhibition (PI3K), and constitutively active constructs (ERK1/2).
- Assessed effects on arterial development, branching morphogenesis, and arteriogenesis in synectin-deficient, atherosclerotic, and adult mice.
Main Results:
- Downregulating PI3K activity or suppressing Akt1 increased ERK1/2 activity in ECs.
- Restored ERK1/2 activation rescued impaired arterial development and branching in synectin-deficient mice and zebrafish.
- Enhanced ERK signaling stimulated arterial growth and arteriogenesis in adult mice, including atherosclerotic models.
Conclusions:
- PI3K-ERK1/2 signaling crosstalk is critical for regulating arterial growth.
- Augmenting ERK signaling by suppressing PI3K effectively promotes arteriogenesis.
