Cdc42 Controls Vascular Network Assembly Through Protein Kinase Cι During Embryonic Vasculogenesis

被引:17
作者
Qi, Yanmei
Liu, Jie
Wu, Xunwei [2 ]
Brakebusch, Cord [3 ]
Leitges, Michael [4 ]
Han, Yaling [5 ]
Corbett, Siobhan A.
Lowry, Stephen F.
Graham, Alan M.
Li, Shaohua [1 ]
机构
[1] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Surg, Div Vasc Surg, New Brunswick, NJ 08903 USA
[2] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Charlestown, MA USA
[3] Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark
[4] Univ Oslo, Biotechnol Ctr Oslo, Oslo, Norway
[5] Shenyang No Hosp, Shenyang, Peoples R China
关键词
angiogenesis; endothelium; signal transduction; vascular biology; CELL-POLARITY; LUMEN FORMATION; BRANCHING MORPHOGENESIS; SHEAR-STRESS; STEM-CELLS; RAC1; GENE; PKC; BETA-1-INTEGRIN; ANGIOGENESIS;
D O I
10.1161/ATVBAHA.111.230144
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective-The goal of this study was to determine the role of Cdc42 in embryonic vasculogenesis and the underlying mechanisms. Methods and Results-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 C iota (PKC iota) is abolished in Cdc42-null endothelial cells, and PKC iota ablation phenocopies the vascular abnormalities of the Cdc42-null EBs. Moreover, the inhibitory phosphorylation of glycogen synthase kinase-3 beta (GSK-3 beta) at Ser9 depends on Cdc42 and PKC iota, and expression of kinase-dead GSK-3 beta in Cdc42-null EBs promotes the formation of linear endothelial segments without branches. These results suggest that PKC iota and GSK-3 beta are downstream effectors of Cdc42 during vascular morphogenesis. Conclusion-Cdc42 controls vascular network assembly but not endothelial lineage differentiation by activating PKC iota during embryonic vasculogenesis. (Arterioscler Thromb Vasc Biol. 2011;31:1861-1870.)
引用
收藏
页码:1861 / U342
页数:12
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