An important role of endothelial hairy-related transcription factors in mouse vascular development

Takashi Morioka, Masahide Sakabe, Tomoko Ioka, Tomoko Iguchi, Ken Mizuta, Miwa Hattammaru, Chihiro Sakai, Munehiro Itoh, Genki E. Sato, Aya Hashimoto, Masahide Fujita, Kazuki Okumura, Mutsumi Araki, Mei Xin, Roger A. Pedersen, Manuel F. Utset, Hiroshi Kimura, Osamu Nakagawa

Research output: Contribution to journalLetter

3 Scopus citations

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 (H1ko/H2ko) 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 (H1ko/H2eko) 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 H1ko/H2ko 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 H1ko/H2eko 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.

Original languageEnglish (US)
Pages (from-to)897-906
Number of pages10
JournalGenesis
Volume52
Issue number11
DOIs
StatePublished - Nov 1 2014

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Keywords

  • Hrt/Hey
  • Mouse embryo
  • Robo4
  • Src family kinases
  • Vascular morphogenesis

ASJC Scopus subject areas

  • Genetics
  • Endocrinology
  • Cell Biology

Cite this

Morioka, T., Sakabe, M., Ioka, T., Iguchi, T., Mizuta, K., Hattammaru, M., Sakai, C., Itoh, M., Sato, G. E., Hashimoto, A., Fujita, M., Okumura, K., Araki, M., Xin, M., Pedersen, R. A., Utset, M. F., Kimura, H., & Nakagawa, O. (2014). An important role of endothelial hairy-related transcription factors in mouse vascular development. Genesis, 52(11), 897-906. https://doi.org/10.1002/dvg.22825