title: Endothelial RAF1/ERK activation regulates arterial morphogenesis.
abstract: Arterial morphogenesis is one of the most critical events during embryonic vascular development. Although arterial fate specification is mainly controlled by the Notch signaling pathway, arterial-venous patterning is modulated by a number of guidance factors. How these pathways are regulated is still largely unknown. Here, we demonstrate that endothelial activation of RAF1/extracellular signal-regulated kinase (ERK) pathway regulates arterial morphogenesis and arterial-venous patterning via Δ/Notch and semaphorin signaling. Introduction of a single amino acid RAF1 mutant (RAF1 Ser259Ala), which renders it resistant to inhibition by phosphorylation, into endothelial cells in vitro induced expression of virtually the entire embryonic arteriogenic program and activated semaphorin 6A-dependent endothelial cell-cell repulsion. In vivo, endothelial-specific expression of RAF1(S259A) during development induced extensive arterial morphogenesis both in the yolk sac and the embryo proper and disrupted arterial-venous patterning. Our results suggest that endothelial ERK signaling is critical for both arteriogenesis and arterial-venous patterning and that RAF1 Ser(259) phosphorylation plays a critical role in preventing unopposed ERK activation.
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Deng
authors.forename: Bruno
authors.initials: B
authors.lastname: Larrivée
authors.forename: Zhen W
authors.initials: ZW
authors.lastname: Zhuang
authors.forename: Deepak
authors.initials: D
authors.lastname: Atri
authors.forename: Filipa
authors.initials: F
authors.lastname: Moraes
authors.forename: Claudia
authors.initials: C
authors.lastname: Prahst
authors.forename: Anne
authors.initials: A
authors.lastname: Eichmann
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
mesh_terms: D000818:Animals; D001158:Arteries / Q000196:embryology* / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism* / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology; D011247:Pregnancy; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D039961:Semaphorins / Q000235:genetics
chemical_list: C504203:Sema6a protein, mouse; D039961:Semaphorins; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases