title: Impaired expression of HIF-2α induces compensatory expression of HIF-1α for the recovery from anemia.
abstract: Erythropoiesis is strongly influenced by the interactions between stromal cells and erythroid progenitors, as well as by a key regulatory factor, erythropoietin (EPO). We previously generated mice with a knockdown mutation of Hif-2α (referred to as kd/kd) and found that these kd/kd mice exhibited normocytic anemia, even though the EPO expression was not severely affected. However, the VCAM-1 expression in spleen endothelial cells (EC), which is regulated by HIF-2α, was impaired, resulting in defective erythroid maturation. A deficiency of HIF-2α clearly led to pancytopenia. However, the critical level of HIF-2α required for erythropoiesis has not yet been elucidated. In this study, we generated HIF-2α knockdown/knockout heterozygous mice (kd/null). Strikingly, anemia was observed in the kd/null mice, but the red blood cell indices were significantly improved compared to those of kd/kd mice. In the spleens of kd/null mice, higher HIF-1α activity and expansion of the red pulp area were observed compared to those of kd/kd mice. Importantly, EC isolated from kd/null spleens showed high expression of VEGF receptors, FLK-1 and FLT-1, which are regulated by HIF-1α instead of HIF-2α under hypoxic conditions. We also found higher expression of phosphorylated ERK and higher proliferative activity in the EC isolated from kd/null mice compared to those from kd/kd mice. While the HIF-2α expression was diminished, HIF-1α bound to the HRE region in the promoters of genes that are normally regulated by HIF-2α. These results suggest that there is a compensatory pathway involving HIF-1α that regulates the expression of some HIF-2α target genes.
authors.affiliation: Graduate School of Comprehensive Human Sciences, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba, Tsukuba, Japan.
authors.forename: Ikki
authors.initials: I
authors.lastname: Tsuboi
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yamashita
authors.forename: Masumi
authors.initials: M
authors.lastname: Nagano
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kimura
authors.forename: Georgina
authors.initials: G
authors.lastname: To'a Salazar
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohneda
mesh_terms: D000740:Anemia / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004900:Erythroblasts; D005786:Gene Expression Regulation / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C501163:Flt1 protein, mouse
keywords: HIF; endothelial cell; erythropoiesis; hypoxia