TY - JOUR
T1 - The microenvironment for erythropoiesis is regulated by HIF-2ά through VCAM-1 in endothelial cells
AU - Yamashita, Toshiharu
AU - Ohneda, Osamu
AU - Sakiyama, Ai
AU - Iwata, Fumiko
AU - Ohneda, Kinuko
AU - Fujii-Kuriyama, Yoshiaki
PY - 2008/8/15
Y1 - 2008/8/15
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2007-11-122648
DO - 10.1182/blood-2007-11-122648
M3 - Article
C2 - 18451309
AN - SCOPUS:51649104761
VL - 112
SP - 1482
EP - 1492
JO - Blood
JF - Blood
SN - 0006-4971
IS - 4
ER -