VEGF-Induced Adult Neovascularization: Recruitment, Retention, and Role of Accessory Cells

Department of Molecular Biology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Cell (Impact Factor: 32.24). 02/2006; 124(1):175-89. DOI: 10.1016/j.cell.2005.10.036
Source: PubMed


Adult neovascularization relies on the recruitment of circulating cells, but their angiogenic roles and recruitment mechanisms are unclear. We show that the endothelial growth factor VEGF is sufficient for organ homing of circulating mononuclear myeloid cells and is required for their perivascular positioning and retention. Recruited bone marrow-derived circulating cells (RBCCs) summoned by VEGF serve a function distinct from endothelial progenitor cells. Retention of RBCCs in close proximity to angiogenic vessels is mediated by SDF1, a chemokine induced by VEGF in activated perivascular myofibroblasts. RBCCs enhance in situ proliferation of endothelial cells via secreting proangiogenic activities distinct from locally induced activities. Precluding RBCCs strongly attenuated the proangiogenic response to VEGF and addition of purified RBCCs enhanced angiogenesis in excision wounds. Together, the data suggest a model for VEGF-programmed adult neovascularization highlighting the essential paracrine role of recruited myeloid cells and a role for SDF1 in their perivascular retention.

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    • "While maturation is a morphological feature of new vessels (pericyte association), stabilization is the functional property of persisting independently of further VEGF stimulation (Dor et al, 2002; Potente et al, 2011) and is a therapeutically relevant property defining the minimum necessary duration of VEGF delivery to achieve a persistent increase in vascularity. Different populations of bone marrow (BM)-derived mononuclear cells also are recruited to the sites of VEGF-induced angiogenesis in adult tissues, where they do not incorporate into the newly formed vessels (Ziegelhoeffer et al, 2004; Zentilin et al, 2006), but exert pro-angiogenic effects by secreting paracrine factors (Grunewald et al, 2006; Korpisalo et al, 2008). In particular, a specific population of monocytes co-expressing CD11b and the VEGF co-receptor Neuropilin-1 (NRP1), and named therefore neuropilin-expressing monocytes (NEM), do not stimulate endothelial proliferation and vascular growth, but specifically favor pericyte and smooth muscle cell recruitment during VEGF-induced angiogenesis by secreting transforming growth factor-b (TGF-b) and platelet-derived growth factor-BB (PDGF-BB) (Zacchigna et al, 2008), leading also to normalization of tumor vessels and inhibiting tumor growth (Carrer et al, 2012). "
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    • "Another means by which CAF promote tumor growth and angiogenesis is the production of the chemokine SDF1. This factor directly stimulates carcinoma cells but also recruits EPC (Orimo et al., 2005) and other bone marrow–derived cells into the tumor tissue, where they are captured in close proximity to angiogenic blood vessels (Grunewald et al., 2006). Other than production of growth factors, CAF also produce proteases, including MMPs (Stetler- Stevenson et al., 1993; Sternlicht et al., 1999; Boire et al., 2005), which stimulate the release of matrix-bound proangiogenic growth factors, thereby promoting angiogenesis and possibly resistance to angiogenic therapy. "
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    • "• Then, VEGF works to induce the expression of multiple proteases including matrix metalloproteinases (MMPs) which leads to dissolution of the extracellular matrix around vessels [18]. • A third VEGF-mediated biological process has been the recruitment of endothelial progenitor cells and other bone marrow-derived cells to the sites where new blood vessels are forming [19] [20]. "
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