CXXC5 is a transcriptional activator of Flk-1 and mediates bone morphogenic protein-induced endothelial cell differentiation and vessel formation

Hyun Yi Kim, Dong Hwa Yang, Song Weon Shin, Mi Yeon Kim, Jae Hyun Yoon, Suhyun Kim, Hae Chul Park, Dong Woo Kang, Dosik Min, Man Wook Hur, Kang Yell Choi

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20 Citations (Scopus)

Abstract

CXXC5 is a member of a small subset of proteins containing CXXC-type zinc-finger domain. Here, we show that CXXC5 is a transcription factor activating Flk-1, a receptor for vascular endothelial growth factor. CXXC5 and Flk-1 were accmulated in nucli and membrane of mouse embryonic stem cells (mESCs), respectively, during their endothelial differentiation. CXXC5 overexpression induced Flk-1 transcription in both endothelium-differentiated mESCs and human umbilical vein endothelial cells (HUVECs). In vitro DNA binding assay showed direct interaction of CXXC5 on the Flk-1 promoter region, and mutation on its DNA-binding motif abolished transcriptional activity. We showed that bone morphorgeneic protein 4 (BMP4) induced CXXC5 transcription in the cells, and inhibitors of BMP signaling suppressed the CXXC5 induction and the consequent Flk-1 induction by BMP4 treatment. CXXC5 knockdown resulted in suppression of BMP4-induced stress fiber formation (56.8±1.3% decrease, P<0.05) and migration (54.6±1.9% decrease, P<0.05) in HUVECs. The in vivo roles of CXXC5 in BMP-signaling-specific vascular development and angiogenesis were shown by specific defect of caudal vein plex vessel formation (57.9±11.8% decrease, P<0.05) in cxxc5 morpholino-injected zebrafish embryos and by supression of BMP4-induced angigogensis in subcutaneously injected Matrigel plugs in CXXC5-/- mice. Overall, CXXC5 is a transcriptional activator for Flk-1, mediating BMP signaling for differentiation and migration of endothelial cell and vessel formation.

Original languageEnglish
Pages (from-to)615-626
Number of pages12
JournalFASEB Journal
Volume28
Issue number2
DOIs
Publication statusPublished - 2014 Jan 1

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Keywords

  • Caudal vein plex vessel formation
  • HUVECs
  • Mouse embryonic stem cells

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology
  • Medicine(all)

Cite this

Kim, H. Y., Yang, D. H., Shin, S. W., Kim, M. Y., Yoon, J. H., Kim, S., Park, H. C., Kang, D. W., Min, D., Hur, M. W., & Choi, K. Y. (2014). CXXC5 is a transcriptional activator of Flk-1 and mediates bone morphogenic protein-induced endothelial cell differentiation and vessel formation. FASEB Journal, 28(2), 615-626. https://doi.org/10.1096/fj.13-236216