title: Notch signaling regulates remodeling and vessel diameter in the extraembryonic yolk sac.
abstract: BACKGROUND
  The signaling cascades that direct the morphological differentiation of the vascular system during early embryogenesis are not well defined. Several signaling pathways, including Notch and VEGF signaling, are critical for the formation of the vasculature in the mouse. To further understand the role of Notch signaling during endothelial differentiation and the genes regulated by this pathway, both loss-of-function and gain-of-function approaches were analyzed in vivo.
  
  
  RESULTS
  Conditional transgenic models were used to expand and ablate Notch signaling in the early embryonic endothelium. Embryos with activated Notch1 signaling in the vasculature displayed a variety of defects, and died soon after E10.5. Most notably, the extraembryonic vasculature of the yolk sac displayed remodeling differentiation defects, with greatly enlarged lumens. These phenotypes were distinct from endothelial loss-of-function of RBPJ, a transcriptional regulator of Notch activity. Gene expression analysis of RNA isolated from the yolk sac endothelia of transgenic embryos indicated aberrant expression in a variety of genes in these models. In particular, a variety of secreted factors, including VEGF and TGF-β family members, displayed coordinate expression defects in the loss-of-function and gain-of-function models.
  
  
  CONCLUSIONS
  Morphological analyses of the in vivo models confirm and expand the understanding of Notch signaling in directing endothelial development, specifically in the regulation of vessel diameter in the intra- and extraembryonic vasculature. Expression analysis of these in vivo models suggests that the vascular differentiation defects may be due to the regulation of key genes through the Notch-RBPJ signaling axis. A number of these genes regulated by Notch signaling encode secreted factors, suggesting that Notch signaling may mediate remodeling and vessel diameter in the extraembryonic yolk sac via autocrine and paracrine cell communication. We propose a role for Notch signaling in elaborating the microenvironment of the nascent arteriole, suggesting novel regulatory connections between Notch signaling and other signaling pathways during endothelial differentiation.
authors.affiliation: Department of Pathology and Laboratory Medicine and Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA. jvivian@kumc.edu
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Copeland
authors.forename: Yi
authors.initials: Y
authors.lastname: Feng
authors.forename: Naveen K
authors.initials: NK
authors.lastname: Neradugomma
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Fields
authors.forename: Jay L
authors.initials: JL
authors.lastname: Vivian
mesh_terms: D000818:Animals; D001483:Base Sequence; D001808:Blood Vessels / Q000196:embryology*; D002454:Cell Differentiation; D004727:Endothelium / Q000196:embryology; D005321:Extraembryonic Membranes / Q000098:blood supply / Q000378:metabolism; D047109:Fetal Development; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D020868:Gene Silencing; D005838:Genotype; D051379:Mice / Q000196:embryology; D008822:Mice, Transgenic; D046228:Microarray Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D015017:Yolk Sac / Q000098:blood supply / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A