The microenvironment for erythropoiesis is regulated by HIF-2ά through VCAM-1 in endothelial cells

Toshiharu Yamashita, Osamu Ohneda, Ai Sakiyama, Fumiko Iwata, Kinuko Ohneda, Yoshiaki Fujii-Kuriyama

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Erythropoiesis is adynamic process regulated by oxygen in vertebrates. Recent evidence has indicated that erythropoietin (Epo) expression is regulated by hypoxia-inducible transcription factors (HIFs), HIF-2α in particular. In this study, we report that knockdown mutation of HIF-2α in mice (kd/kd) results in normocytc anemia, despite Epo induction in response to hypoxia not being severely affected. Transplantation analyses clearly demonstrated that the hematopoietic microenvironment, but not the hematopoietic cells, was altered in kd/kd. Furthermore, cell-type specific recovery of HIF-2α expression in endothelial cells (ECs) abrogated the anemic condition of the kd/kd mice, indicating that HIF-2α in EC plays an essential role in supporting erythropoiesis. In the absence of HIF-2α. the expression of vascular adhesion molecule-1 (VCAM-1) was reduced significantly and restoration of VCAM-1 expression in kd/kd ECs enhanced the development of erythroid progenitors. Finally, a chromatin immunoprecipitation assay and a reporter assay indicated that VCAM-1 gene transcription is directly regulated by HIF- 2α. These data suggest that the hematopoietic microenvironment required for erythropoiesis is dynamically regulated by oxygen through the functions of HIF-2α in ECs.

Original languageEnglish
Pages (from-to)1482-1492
Number of pages11
JournalBlood
Volume112
Issue number4
DOIs
Publication statusPublished - 2008 Aug 15
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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