HIFα induces the recruitment of bone marrow‐derived vascular modulatory cells to regulate tumor angiogenesis

Several studies have shown that neovascularization of tumors is not solely restricted to activation of differentiated endothelial cells but can also involve the recruitment of bone marrow‐derived cells to active sites of vascular remodeling in tumors. These BMDCs include endothelial progenitor cells (EPC) and pericyte progenitor cells (PPC). While EPCs incorporate into the vasculature and differentiate into endothelial cells, PPCs envelope blood vessels and mature into pericytes and vascular smooth muscle cells. In addition, CD45+ cells of the monocytic lineage that function as vascular modulators, but are not physically part of the vasculature present the biggest and most heterogeneous group. Recruitment of BMDC, specifically of EPC, can vary substantially between tumor types and stages but little is known about factors that dictate the mobilization of BMDC from the bone marrow into the blood stream and their recruitment and retention into the tumor. The most prominent factors identified thus far include VEGF, PlGF and PDGF‐B acting as mobilization factors of EPCs and PPCs respectively and SDF1α, which acts to retain CXCR4+ BMDCs within tumors. We hypothesize that hypoxic conditions in tumors may promote neovascularization by mediating BMDC recruitment. We demonstrate that HIF1α, the direct effector of hypoxia, partly through increases in SDF1α, induces recruitment of bone marrow (BM)‐derived CD45+ myeloid cells containing Tie2+, VEGFR1+, CD11b+ and F4/80+ subpopulations, as well as endothelial and pericyte progenitor cells to promote neovascularization in glioblastoma. MMP‐9 activity of BM‐CD45+ cells is essential and sufficient to initiate angiogenesis by increasing VEGF bioavailability. In the absence of HIF1α, SDF1α levels decrease, fewer BM‐derived cells are recruited to the tumors, decreasing MMP‐9 and solubilization of VEGF.