HIF prolyl hydroxylase inhibitor FG-4497 enhances mouse hematopoietic stem cell mobilization via VEGFR2/KDR
| Autor: | Andrew C. Perkins, Ingrid G. Winkler, Thomas Keech, Marion E. G. Brunck, Whitney Fleming, Gail Walkinshaw, Taichi Matsumoto, Jean-Pierre Levesque, Julie M. Davies, Kavita Bisht, Bianca Nowlan, Graham Magor, Crystal McGirr, Lee A. Flippin |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Hematopoiesis and Stem Cells Pyridines Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Progenitor cell Hematopoietic Stem Cell Mobilization Chemistry Plerixafor Prolyl-Hydroxylase Inhibitors Kinase insert domain receptor Hematology HIF prolyl-hydroxylase inhibitor respiratory system Isoquinolines Vascular Endothelial Growth Factor Receptor-2 Cell biology Mice Inbred C57BL Vascular endothelial growth factor A Haematopoiesis 030220 oncology & carcinogenesis cardiovascular system Phthalazines Procollagen-proline dioxygenase circulatory and respiratory physiology 030215 immunology medicine.drug |
| Zdroj: | Blood Advances. 3:406-418 |
| ISSN: | 2473-9537 2473-9529 |
| Popis: | In normoxia, hypoxia-inducible transcription factors (HIFs) are rapidly degraded within the cytoplasm as a consequence of their prolyl hydroxylation by oxygen-dependent prolyl hydroxylase domain (PHD) enzymes. We have previously shown that hematopoietic stem and progenitor cells (HSPCs) require HIF-1 for effective mobilization in response to granulocyte colony-stimulating factor (G-CSF) and CXCR4 antagonist AMD3100/plerixafor. Conversely, HIF PHD inhibitors that stabilize HIF-1 protein in vivo enhance HSPC mobilization in response to G-CSF or AMD3100 in a cell-intrinsic manner. We now show that extrinsic mechanisms involving vascular endothelial growth factor receptor-2 (VEGFR2), via bone marrow (BM) endothelial cells, are also at play. PTK787/vatalanib, a tyrosine kinase inhibitor selective for VEGFR1 and VEGFR2, and neutralizing anti-VEGFR2 monoclonal antibody DC101 blocked enhancement of HSPC mobilization by FG-4497. VEGFR2 was absent on mesenchymal and hematopoietic cells and was detected only in Sca1+ endothelial cells in the BM. We propose that HIF PHD inhibitor FG-4497 enhances HSPC mobilization by stabilizing HIF-1α in HSPCs as previously demonstrated, as well as by activating VEGFR2 signaling in BM endothelial cells, which facilitates HSPC egress from the BM into the circulation. |
| Databáze: | OpenAIRE |
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