ERK5 MAPK regulates embryonic angiogenesis and acts as a hypoxia-sensitive repressor of vascular endothelial growth factor expression.
During angiogenesis, endothelial cells undergo proliferation, reorganization, and stabilization to establish a mature vascular network. This process is critical for establishing a functional circulatory system during development and contributes to the pathological process of tumor growth. Here we report that embryos deficient for the ERK5 MAPK die between embryonic days 10.5 and 11.5 with angiogenic failure and cardiovascular defects. We show that ERK5 deficiency leads to an increased expression of the vascular endothelial growth factor (VEGF), dysregulation of which has been shown to impede angiogenic remodeling and vascular stabilization. Our data also reveal that ERK5 negatively regulates transcription from the vegf locus during hypoxic responses. Importantly, ERK5 is required at an earlier developmental stage than p38alpha, and p38alpha does not compensate for ERK5 deficiency. These results demonstrate that ERK5 plays a specific role in the regulation of early angiogenesis.
Sohn
Sue J
SJ
Department of Molecular and Cell Biology, Division of Immunology and Cancer Research Laboratory, University of California, Berkeley, California 94720-3200, USA.
Sarvis
Brieana K
BK
Cado
Dragana
D
Winoto
Astar
A
D000818:Animals; D015687:Cell Hypoxia; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005091:Exons; D005260:Female; D005313:Fetal Death; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007438:Introns; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011247:Pregnancy; D012097:Repressor Proteins / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D015017:Yolk Sac / Q000098:blood supply / Q000473:pathology
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012097:Repressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases