title: An important role of endothelial hairy-related transcription factors in mouse vascular development.
abstract: The Hairy-related transcription factor family of Notch- and ALK1-downstream transcriptional repressors, called Hrt/Hey/Hesr/Chf/Herp/Gridlock, has complementary and indispensable functions for vascular development. While mouse embryos null for either Hrt1/Hey1 or Hrt2/Hey2 did not show early vascular phenotypes, Hrt1/Hey1; Hrt2/Hey2 double null mice (H1(ko) /H2(ko) ) showed embryonic lethality with severe impairment of vascular morphogenesis. It remained unclear, however, whether Hrt/Hey functions are required in endothelial cells or vascular smooth muscle cells. In this study, we demonstrate that mice with endothelial-specific deletion of Hrt2/Hey2 combined with global Hrt1/Hey1 deletion (H1(ko) /H2(eko) ) show abnormal vascular morphogenesis and embryonic lethality. Their defects were characterized by the failure of vascular network formation in the yolk sac, abnormalities of embryonic vascular structures and impaired smooth muscle cell recruitment, and were virtually identical to the H1(ko) /H2(ko) phenotypes. Among signaling molecules implicated in vascular development, Robo4 expression was significantly increased and activation of Src family kinases was suppressed in endothelial cells of H1(ko) /H2(eko) embryos. The present study indicates an important role of Hrt1/Hey1 and Hrt2/Hey2 in endothelial cells during early vascular development, and further suggests involvement of Robo4 and Src family kinases in the mechanisms of embryonic vascular defects caused by the Hrt/Hey deficiency.
authors.affiliation: Laboratory for Cardiovascular System Research, Nara Medical University Advanced Medical Research Center, Kashihara, Nara, Japan; The Second Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Morioka
authors.forename: Masahide
authors.initials: M
authors.lastname: Sakabe
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ioka
authors.forename: Tomoko
authors.initials: T
authors.lastname: Iguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Mizuta
authors.forename: Miwa
authors.initials: M
authors.lastname: Hattammaru
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sakai
authors.forename: Munehiro
authors.initials: M
authors.lastname: Itoh
authors.forename: Genki E
authors.initials: GE
authors.lastname: Sato
authors.forename: Aya
authors.initials: A
authors.lastname: Hashimoto
authors.forename: Masahide
authors.initials: M
authors.lastname: Fujita
authors.forename: Kazuki
authors.initials: K
authors.lastname: Okumura
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Araki
authors.forename: Mei
authors.initials: M
authors.lastname: Xin
authors.forename: Roger A
authors.initials: RA
authors.lastname: Pedersen
authors.forename: Manuel F
authors.initials: MF
authors.lastname: Utset
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002319:Cardiovascular System / Q000196:embryology*; D004727:Endothelium / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D012097:Repressor Proteins; C405694:Hairy, HRT1 protein; C485778:Hey2 protein, mouse; C540792:Robo4 protein, mouse
keywords: Hrt/Hey; Robo4; Src family kinases; mouse embryo; vascular morphogenesis