Ets1 and Ets2 are required for endothelial cell survival during embryonic angiogenesis.
The ras/Raf/Mek/Erk pathway plays a central role in coordinating endothelial cell activities during angiogenesis. Transcription factors Ets1 and Ets2 are targets of ras/Erk signaling pathways that have been implicated in endothelial cell function in vitro, but their precise role in vascular formation and function in vivo remains ill-defined. In this work, mutation of both Ets1 and Ets2 resulted in embryonic lethality at midgestation, with striking defects in vascular branching having been observed. The action of these factors was endothelial cell autonomous as demonstrated using Cre/loxP technology. Analysis of Ets1/Ets2 target genes in isolated embryonic endothelial cells demonstrated down-regulation of Mmp9, Bcl-X(L), and cIAP2 in double mutants versus controls, and chromatin immunoprecipitation revealed that both Ets1 and Ets2 were loaded at target promoters. Consistent with these observations, endothelial cell apoptosis was significantly increased both in vivo and in vitro when both Ets1 and Ets2 were mutated. These results establish essential and overlapping functions for Ets1 and Ets2 in coordinating endothelial cell functions with survival during embryonic angiogenesis.
Department of Molecular and Cellular Biochemistry, The OhioState University, Columbus, OH 43210, USA.
Guo
G
Wei
Ruchika
R
Srinivasan
Carmen Z
CZ
Cantemir-Stone
Sudarshana M
SM
Sharma
Ramasamy
R
Santhanam
Michael
M
Weinstein
Natarajan
N
Muthusamy
Albert K
AK
Man
Robert G
RG
Oshima
Gustavo
G
Leone
Michael C
MC
Ostrowski
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001808:Blood Vessels / Q000196:embryology / Q000648:ultrastructure; D002470:Cell Survival / Q000235:genetics; D002678:Chimera; D004487:Edema / Q000196:embryology / Q000235:genetics; D004624:Embryo Transfer; D047108:Embryonic Development / Q000235:genetics*; D042783:Endothelial Cells / Q000166:cytology*; D005313:Fetal Death / Q000235:genetics / Q000473:pathology; D005315:Fetal Diseases / Q000235:genetics / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D006470:Hemorrhage / Q000196:embryology / Q000235:genetics; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010641:Phenotype; D050784:Proto-Oncogene Protein c-ets-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050787:Proto-Oncogene Protein c-ets-2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
C494042:Ets1 protein, mouse; C494070:Ets2 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D050787:Proto-Oncogene Protein c-ets-2