HIF prolyl hydroxylase inhibitor FG-4497 enhances mouse hematopoietic stem cell mobilization via VEGFR2/KDR

• Published in: Blood advances 2019-02, Vol.3 (3), p.406-418
• Main Authors: Bisht, Kavita, Brunck, Marion E., Matsumoto, Taichi, McGirr, Crystal, Nowlan, Bianca, Fleming, Whitney, Keech, Thomas, Magor, Graham, Perkins, Andrew C., Davies, Julie, Walkinshaw, Gail, Flippin, Lee, Winkler, Ingrid G., Levesque, Jean-Pierre
• Format: Article
• Language: English
• Subjects: Animals; Hematopoiesis and Stem Cells; Hematopoietic Stem Cell Mobilization - methods; Isoquinolines - pharmacology; Male; Mice; Mice, Inbred C57BL; Phthalazines - pharmacology; Prolyl-Hydroxylase Inhibitors - pharmacology; Pyridines - pharmacology; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2018017566

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. [Display omitted]