#3777 ACTIVATION OF HYPOXIA-INDUCIBLE FACTORS IN ERYTHROID PROGENITOR CELLS RESULTS IN DEFECTIVE ERYTHROPOIESIS

Abstract

Abstract Background and Aims Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) activates HIF in renal pericytes and fibroblasts to promote erythropoietin production and erythropoiesis. However, the effects of HIF stabilization in the erythroid lineage are not clear. We aim to study the effects of erythroid lineage-specific stabilization of HIF on erythropoiesis by preclinical models. Method EporGFP-Cre/+;VhlF/F mice were used to achieve erythroid lineage-specific stabilization of HIF. Surface expression of TER-119, CD44, and forward scatter (FSC) were used to define erythroblast, reticulocyte, and red blood cell in the bone marrow. Expression of propidium iodide and surface annexin V were used to define apoptosis. Stress erythropoiesis was induced by subcutaneous administration of phenylhydrazine. Results Compared with littermate VhlF/F mice, EporGFP-Cre/+;VhlF/F mice had decreased hematocrit, decreased percentage of erythroblasts in the bone marrow, and increased apoptosis of erythroblasts in the bone marrow under steady state. These phenotypes of defective erythropoiesis were normalized in mice harboring concomitant Vhl, Hif1a, and Hif2a deletion (EporGFP-Cre/+;VhlF/F;Hif1aF/F;Hif2aF/Fmice). Although macrophages in the bone marrow also express Epor, macrophage-specific Vhl deletion in either Tg(Csf1r-CreESR1);VhlF/F or Lyz2Cre/+;VhlF/F mice did not result in defective erythropoiesis. During stress erythropoiesis, compared with littermate VhlF/F mice, EporGFP-Cre/+;VhlF/F mice had similar hematocrit, lower percentage of erythroblast in the bone marrow, and increased percentage of erythroblast in the spleen. Conclusion Vhl deletion in erythroid progenitor cells impairs erythropoiesis in murine bone marrow in the steady state. The phenotypes of defective erythropoiesis were partially reversed during stress erythropoiesis.