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An important role of endothelial hairy‐related transcription factors in mouse vascular development
Author(s) -
Morioka Takashi,
Sakabe Masahide,
Ioka Tomoko,
Iguchi Tomoko,
Mizuta Ken,
Hattammaru Miwa,
Sakai Chihiro,
Itoh Munehiro,
Sato Genki E.,
Hashimoto Aya,
Fujita Masahide,
Okumura Kazuki,
Araki Mutsumi,
Xin Mei,
Pedersen Roger A.,
Utset Manuel F.,
Kimura Hiroshi,
Nakagawa Osamu
Publication year - 2014
Publication title -
genesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.093
H-Index - 110
eISSN - 1526-968X
pISSN - 1526-954X
DOI - 10.1002/dvg.22825
Subject(s) - biology , microbiology and biotechnology , transcription factor , embryonic stem cell , vascular smooth muscle , phenotype , morphogenesis , vascular endothelial growth factor b , vascular endothelial growth factor a , cancer research , vascular endothelial growth factor , genetics , endocrinology , gene , smooth muscle , vegf receptors
Summary 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. genesis 52:897–906, 2014. © 2014 Wiley Periodicals, Inc.