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 Blood, 15 August 2008, Vol. 112, No. 4, pp. 1482-1492.
Prepublished online as a Blood First Edition Paper on May 1, 2008; DOI 10.1182/blood-2007-11-122648.

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RED CELLS

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

Toshiharu Yamashita*,1, Osamu Ohneda*,1, Ai Sakiyama1, Fumiko Iwata1, Kinuko Ohneda2, and Yoshiaki Fujii-Kuriyama3

1 Graduate School of Comprehensive Human Sciences, Department of Regenerative Medicine, University of Tsukuba, Tsukuba; 2 Laboratory of Molecular Pathophysiology, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki; and 3 Center for TARA, University of Tsukuba, Tsukuba, Japan

Erythropoiesis is a dynamic process regulated by oxygen in vertebrates. Recent evidence has indicated that erythropoietin (Epo) expression is regulated by hypoxia-inducible transcription factors (HIFs), HIF-2{alpha} in particular. In this study, we report that knockdown mutation of HIF-2{alpha} in mice (kd/kd) results in normocytic 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-2{alpha} expression in endothelial cells (ECs) abrogated the anemic condition of the kd/kd mice, indicating that HIF-2{alpha} in EC plays an essential role in supporting erythropoiesis. In the absence of HIF-2{alpha}, 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-2{alpha}. These data suggest that the hematopoietic microenvironment required for erythropoiesis is dynamically regulated by oxygen through the functions of HIF-2{alpha} in ECs.


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Related Article in Blood Online:

Erythropoiesis—once more HIF!
Joachim Fandrey
Blood 2008 112: 931-932. [Full Text] [PDF]





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