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HIF prolyl hydroxylase inhibitor FG-4497 enhances mouse hematopoietic stem cell mobilization via VEGFR2/KDR
- Source :
- Blood Advances. 3:406-418
- Publication Year :
- 2019
- Publisher :
- American Society of Hematology, 2019.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 24739537 and 24739529
- Volume :
- 3
- Database :
- OpenAIRE
- Journal :
- Blood Advances
- Accession number :
- edsair.doi.dedup.....723ae274401a19004dd45bd902268a1b