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EphB4 forward signalling mediates angiogenesis caused by CCM3/PDCD10-ablation
Chao You1,2, Kai Zhao1,2, Philipp Dammann1
1Department of Neurosurgery, University of Duisburg-Essen, Essen, Germany.
Journal of Cellular and Molecular Medicine
|April 4, 2017
Summary
Loss of CCM3 protein (Cellular Communication Module 3) in endothelial cells activates EphB4 signaling, driving angiogenesis. This pathway, involving DLL4/Notch and Erk1/2, offers therapeutic targets for conditions like cerebral cavernous malformation and tumors.
Area of Science:
- Molecular Biology
- Cell Biology
- Vascular Biology
Background:
- Cellular Communication Module 3 (CCM3), also known as PDCD10, is crucial for vascular development and maturation.
- Loss-of-function mutations in CCM3 are linked to cerebral cavernous malformation (CCM).
- Previous studies indicated CCM3 knockdown promotes angiogenesis and tumor growth by affecting DLL4-Notch signaling.
Purpose of the Study:
- To elucidate the specific signaling pathway involved in CCM3-ablation-mediated angiogenesis.
- To investigate the role of EphB4 signaling in the context of CCM3 deficiency.
- To explore potential therapeutic strategies targeting this pathway.
Main Methods:
- Silencing of endothelial CCM3 using knockdown techniques.
- Analysis of EphB4 mRNA and protein expression and kinase activity.
- Assessment of Erk1/2 activation and its modulation by EphB4 inhibition (NVP-BHG712).
- In vitro and in vivo assays to evaluate the hyper-angiogenic phenotype.
- Investigation of the relationship between EphB4 signaling and DLL4/Notch signaling.
Main Results:
- Silencing CCM3 significantly upregulated EphB4 expression and kinase activity.
- CCM3 knockdown led to Erk1/2 activation, which was reversed by an EphB4 inhibitor.
- Inhibition of EphB4 kinase activity rescued the hyper-angiogenic phenotype induced by CCM3 knockdown.
- EphB4 forward signaling activation was found to be downstream of DLL4/Notch signaling.
Conclusions:
- Angiogenesis induced by CCM3 silencing is mediated by the activation of EphB4 forward signaling.
- The identified signaling pathway (CCM3-DLL4/Notch-EphB4-Erk1/2) provides insight into CCM3-ablation-mediated angiogenesis.
- This pathway represents a potential therapeutic target for aberrant angiogenesis in CCM and vascular tumors.