The microenvironment for erythropoiesis is regulated by HIF-2alpha through VCAM-1 in endothelial cells.
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-2alpha in particular. In this study, we report that knockdown mutation of HIF-2alpha 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-2alpha expression in endothelial cells (ECs) abrogated the anemic condition of the kd/kd mice, indicating that HIF-2alpha in EC plays an essential role in supporting erythropoiesis. In the absence of HIF-2alpha, 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-2alpha. These data suggest that the hematopoietic microenvironment required for erythropoiesis is dynamically regulated by oxygen through the functions of HIF-2alpha in ECs.
Yamashita
Toshiharu
T
Department of Regenerative Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Ohneda
Osamu
O
Sakiyama
Ai
A
Iwata
Fumiko
F
Ohneda
Kinuko
K
Fujii-Kuriyama
Yoshiaki
Y
D000740:Anemia / Q000209:etiology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000502:physiology*; D042783:Endothelial Cells / Q000737:chemistry; D004920:Erythropoiesis; D004921:Erythropoietin / Q000235:genetics; D005786:Gene Expression Regulation; D018380:Hematopoietic Stem Cell Transplantation; D051379:Mice; D018345:Mice, Knockout; D010100:Oxygen / Q000502:physiology; D014158:Transcription, Genetic; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D010100:Oxygen; D019010:Vascular Cell Adhesion Molecule-1; D000099162:Endothelial PAS Domain-Containing Protein 1