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.

Download full-text


Available from: Myriam Grunewald, Sep 29, 2015
38 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: VEGF is widely investigated for therapeutic angiogenesis, but while short-term delivery is desirable for safety, it is insufficient for new vessel persistence, jeopardizing efficacy. Here, we investigated whether and how VEGF dose regulates nascent vessel stabilization, to identify novel therapeutic targets. Monoclonal populations of transduced myoblasts were used to homogeneously express specific VEGF doses in SCID mouse muscles. VEGF was abrogated after 10 and 17 days by Aflibercept treatment. Vascular stabilization was fastest with low VEGF, but delayed or prevented by higher doses, without affecting pericyte coverage. Rather, VEGF dose-dependently inhibited endothelial Semaphorin3A expression, thereby impairing recruitment of Neuropilin-1-expressing monocytes (NEM), TGF-β1 production and endothelial SMAD2/3 activation. TGF-β1 further initiated a feedback loop stimulating endothelial Semaphorin3A expression, thereby amplifying the stabilizing signals. Blocking experiments showed that NEM recruitment required endogenous Semaphorin3A and that TGF-β1 was necessary to start the Semaphorin3A/NEM axis. Conversely, Semaphorin3A treatment promoted NEM recruitment and vessel stabilization despite high VEGF doses or transient adenoviral delivery. Therefore, VEGF inhibits the endothelial Semaphorin3A/NEM/TGF-β1 paracrine axis and Semaphorin3A treatment accelerates stabilization of VEGF-induced angiogenesis. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    EMBO Molecular Medicine 08/2015; DOI:10.15252/emmm.201405003 · 8.67 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The concept of antiangiogenic therapy in cancer treatment has led to the approval of different agents, most of them targeting the well known vascular endothelial growth factor pathway. Despite promising results in preclinical studies, the efficacy of antiangiogenic therapy in the clinical setting remains limited. Recently, awareness has emerged on resistance to antiangiogenic therapies. It has become apparent that the intricate complex interplay between tumors and stromal cells, including endothelial cells and associated mural cells, allows for escape mechanisms to arise that counteract the effects of these targeted therapeutics. Here, we review and discuss known and novel mechanisms that contribute to resistance against antiangiogenic therapy and provide an outlook to possible improvements in therapeutic approaches.
    Pharmacological Reviews 03/2015; 67:441-461. · 17.10 Impact Factor
  • Source
    • "• 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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The prognosis of advanced gastric cancer has been dreadful with the majority of patients dying of their disease within 1 year of the diagnosis. In the advanced stage several therapeutic options can be discussed, including molecular targeted agents, but biological predicting factors are lacking. A number of molecular targets have been studied over the last decade bringing to several phase II studies; however very few agents moved into phase III clinical trials. The VEGFR-2 inhibitor monoclonal antibody Ramucirumab has been recently approved in advanced progressing gastric cancer. This article reviews the basic science as well as clinical data of VEGF signaling in advanced gastric cancer with special emphasis on the different VEGF targeting agents tested previously in this disease.
    Critical Reviews in Oncology/Hematology 12/2014; 93(1). DOI:10.1016/j.critrevonc.2014.05.012 · 4.03 Impact Factor
Show more