Erk1 and Erk2 regulate endothelial cell proliferation and migration during mouse embryonic angiogenesis.
Angiogenesis is a complex process orchestrated by both growth factors and cell adhesion and is initiated by focal degradation of the vascular basement membrane with subsequent migration and proliferation of endothelial cells. The Ras/Raf/MEK/ERK pathway is required for EC function during angiogenesis. Although in vitro studies implicate ERK1 and ERK2 in endothelial cell survival, their precise role in angiogenesis in vivo remains poorly defined. Cre/loxP technology was used to inactivate Erk1 and Erk2 in endothelial cells during murine development, resulting in embryonic lethality due to severely reduced angiogenesis. Deletion of Erk1 and Erk2 in primary endothelial cells resulted in decreased cell proliferation and migration, but not in increased apoptosis. Expression of key cell cycle regulators was diminished in the double knockout cells, and decreased DNA synthesis could be observed in endothelial cells during embryogenesis. Interestingly, both Paxillin and Focal Adhesion Kinase were expressed at lower levels in endothelial cells lacking Erk1 and Erk2 both in vivo and in vitro, leading to defects in the organization of the cytoskeleton and in cell motility. The regulation of Paxillin and Focal Adhesion Kinase expression occurred post-transcriptionally. These results demonstrate that ERK1 and ERK2 coordinate endothelial cell proliferation and migration during angiogenesis.
Srinivasan
Ruchika
R
Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio, United States of America.
Zabuawala
Tahera
T
Huang
Hong
H
Zhang
Jianying
J
Gulati
Parul
P
Fernandez
Soledad
S
Karlo
J Colleen
JC
Landreth
Gary E
GE
Leone
Gustavo
G
Ostrowski
Michael C
MC
D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D020964:Embryo Loss / Q000201:enzymology / Q000473:pathology; D004622:Embryo, Mammalian / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D042783:Endothelial Cells / Q000166:cytology* / Q000201:enzymology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000201:enzymology; D018919:Neovascularization, Physiologic; D051419:Paxillin / Q000378:metabolism
D000199:Actins; D051419:Paxillin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3