Submitted November 9, 2007
Accepted March 24, 2008
The microenvironment for erythropoiesis is regulated by HIF-2
through VCAM-1 in endothelial cells
Toshiharu Yamashita, Osamu Ohneda*, Ai Sakiyama, Fumiko Iwata, Kinuko Ohneda, and Yoshiaki Fujii-Kuriyama
Graduate School of Comprehensive Human Sciences, Department of Regenerative Medicine, University of Tsukuba, Tsukuba, Japan
Laboratory of Molecular Pathophysiology, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Japan
Center for TARA, University of Tsukuba, Tsukuba, Japan
* Corresponding author; email: oohneda{at}md.tsukuba.ac.jp.
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
in particular. In this study, we report that knockdown mutation of HIF-2 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 expression in endothelial cells (EC) abrogated the anemic condition of the kd/kd mice, indicating that HIF-2 in EC plays an essential role in supporting erythropoiesis. In the absence of HIF-2, the expression of vascular adhesion molecule-1 (VCAM-1) was reduced significantly and restoration of VCAM-1 expression in kd/kd EC 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. These data suggest that the hematopoietic microenvironment required for erythropoiesis is dynamically regulated by oxygen through the functions of HIF-2 in EC.
