Cdc42 controls vascular network assembly through protein kinase Cι during embryonic vasculogenesis.
Arterioscler Thromb Vasc Biol
; 31(8): 1861-70, 2011 Aug.
Article
en En
| MEDLINE
| ID: mdl-21659643
ABSTRACT
OBJECTIVE:
The goal of this study was to determine the role of Cdc42 in embryonic vasculogenesis and the underlying mechanisms. METHODS ANDRESULTS:
By using genetically modified mouse embryonic stem (ES) cells, we demonstrate that ablation of the Rho GTPase Cdc42 blocks vascular network assembly during embryoid body (EB) vasculogenesis without affecting endothelial lineage differentiation. Reexpression of Cdc42 in mutant EBs rescues the mutant phenotype, establishing an essential role for Cdc42 in vasculogenesis. Chimeric analysis revealed that the vascular phenotype is caused by inactivation of Cdc42 in endothelial cells rather than surrounding cells. Endothelial cells isolated from Cdc42-null EBs are defective in directional migration and network assembly. In addition, activation of atypical protein kinase Cι (PKCι) is abolished in Cdc42-null endothelial cells, and PKCι ablation phenocopies the vascular abnormalities of the Cdc42-null EBs. Moreover, the inhibitory phosphorylation of glycogen synthase kinase-3ß (GSK-3ß) at Ser9 depends on Cdc42 and PKCι, and expression of kinase-dead GSK-3ß in Cdc42-null EBs promotes the formation of linear endothelial segments without branches. These results suggest that PKCι and GSK-3ß are downstream effectors of Cdc42 during vascular morphogenesis.CONCLUSIONS:
Cdc42 controls vascular network assembly but not endothelial lineage differentiation by activating PKCι during embryonic vasculogenesis.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Vasos Sanguíneos
/
Proteína Quinasa C
/
Neovascularización Fisiológica
/
Proteína de Unión al GTP cdc42
/
Isoenzimas
Límite:
Animals
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Asunto de la revista:
ANGIOLOGIA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos