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

Kavita Bisht, Marion E. Brunck, Taichi Matsumoto, Crystal McGirr, Bianca Nowlan, Whitney Fleming, Thomas Keech, Graham Magor, Andrew C. Perkins, Julie Davies, Gail Walkinshaw, Lee Flippin, Ingrid G. Winkler and Jean-Pierre Levesque

Key Points

  • VEGFR1/2 kinase inhibitor and neutralizing anti-VEGFR2 antibody block PHD inhibitor FG-4497–mediated increase in HSPC mobilization.

  • The inhibitory effect of anti-VEGFR2 on HSPC mobilization is likely HSPC extrinsic, as VEGFR2 is only detected in BM endothelial cells.

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.

  • Submitted February 17, 2018.
  • Accepted January 6, 2019.
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