| Objective:MEKK3(mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase3) is a highly conserved member of MAP3K (mitogen-activated protein kinase kinase kinase) super family. MEKK3has been identified to be expressed in multiple tissues. MEKK3is crucial in mural embryonic early development. Knockout of MEKK3gene can cause angiogenesis deficiency in mural embryo and de-structure in yolk sac, which lead to embryo lethality and reveal a role MEKK3plays in angiogenesis. This study focus on the effect of MEKK3has on angiogenesis, and trying to find the mechanism involved.Method:in vivo experiments via conditional or inducible MEKK3gene knockout mice including morphological observation and immunohistochemistry study the function of MEKK3in angiogenesis. In vitro experiments, such as cellular biochemistry, cell culture, RT-PCR and Western Blot, provide a in-sight way to investigate MEKK3-mediated signaling involved in angiogenesis.Results:MEKK3knockout cause angiogenesis deficiency:(1) without MEKK3, the phosphorylation in R-Smad linker region reduced, BMP9/TGF-β and Notch signaling activated, result in a increased expression of there downstream targets (Ids, Hes and Hey). Through this pathway, the function of vascular endothelial tip cell can be greatly impaired. Thus angiogenesis rate can be slowed down even stopped;(2) without MEKK3, β1-Integrin-PKC/Par3/Par6signaling pathway would be altered, the polarity of vascular endothelial cells would be disturbed. Endothelial cells are arranged without organization and can not form a lumen, which can be a cause of blood flow obstruction and hemorrhage.Conclusion:MEKK3gene knockout can block angiogenesis and impair blood vessel function. |
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