Fantin, A, Vieira, JM, Gestri, G, Denti, L, Schwarz, Q, Prykhozhij, S et al.. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116: 829-840

UCL Institute of Ophthalmology, University College London, London, United Kingdom.
Blood (Impact Factor: 10.45). 08/2010; 116(5):829-40. DOI: 10.1182/blood-2009-12-257832
Source: PubMed


Blood vessel networks expand in a 2-step process that begins with vessel sprouting and is followed by vessel anastomosis. Vessel sprouting is induced by chemotactic gradients of the vascular endothelial growth factor (VEGF), which stimulates tip cell protrusion. Yet it is not known which factors promote the fusion of neighboring tip cells to add new circuits to the existing vessel network. By combining the analysis of mouse mutants defective in macrophage development or VEGF signaling with live imaging in zebrafish, we now show that macrophages promote tip cell fusion downstream of VEGF-mediated tip cell induction. Macrophages therefore play a hitherto unidentified and unexpected role as vascular fusion cells. Moreover, we show that there are striking molecular similarities between the pro-angiogenic tissue macrophages essential for vascular development and those that promote the angiogenic switch in cancer, including the expression of the cell-surface proteins TIE2 and NRP1. Our findings suggest that tissue macrophages are a target for antiangiogenic therapies, but that they could equally well be exploited to stimulate tissue vascularization in ischemic disease.

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    • "A growing number of non-immune functions have been attributed to macrophages in other tissues. For example, macrophages are involved in vascular development of the fetal brain (Fantin et al., 2010). In the juvenile and adult testis, macrophages are intimately associated with Leydig cells and promote steroidogenesis (Cohen et al., 1997; Gaytan et al., 1994; Hutson, 2006), although the mechanism through which this interaction is mediated is not entirely clear. "
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    ABSTRACT: The testis produces sperm throughout the male reproductive lifespan by balancing self-renewal and differentiation of spermatogonial stem cells (SSCs). Part of the SSC niche is thought to lie outside the seminiferous tubules of the testis; however, specific interstitial components of the niche that regulate spermatogonial divisions and differentiation remain undefined. We identified distinct populations of testicular macrophages, one of which lies on the surface of seminiferous tubules, in close apposition to areas of tubules enriched for undifferentiated spermatogonia. These macrophages express spermatogonial proliferation- and differentiation-inducing factors, such as colony-stimulating factor 1 (CSF1) and enzymes involved in retinoic acid (RA) biosynthesis. We show that transient depletion of macrophages leads to a disruption in spermatogonial differentiation. These findings reveal an unexpected role for macrophages in the spermatogonial niche in the testis and raise the possibility that macrophages play previously unappreciated roles in stem/progenitor cell regulation in other tissues. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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    • "At E12.5, heterozygous mutants had formed an extensive SVP with a small but statistically significant reduction in branchpoints (Figures 1G, 1H, and 1K). Immunolabeling with a previously validated antibody for NRP1 (Fantin et al., 2010) showed reduced NRP1 levels in heterozygous compared to wild-type brains, especially in vessel sprouts (Figure S1, related to Figure 1), which correlated with reduced mRNA levels (see below). In contrast to heterozygous mutants, homozygous mutants lacked the SVP and instead formed large vascular tufts in the subventricular zone (Figure 1I, clear arrowheads), as previously reported (Fantin et al., 2013a; Gerhardt et al., 2004). "
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    ABSTRACT: Sprouting blood vessels are led by filopodia-studded endothelial tip cells that respond to angiogenic signals. Mosaic lineage tracing previously revealed that NRP1 is essential for tip cell function, although its mechanistic role in tip cells remains poorly defined. Here, we show that NRP1 is dispensable for genetic tip cell identity. Instead, we find that NRP1 is essential to form the filopodial bursts that distinguish tip cells morphologically from neighboring stalk cells, because it enables the extracellular matrix (ECM)-induced activation of CDC42, a key regulator of filopodia formation. Accordingly, NRP1 knockdown and pharmacological CDC42 inhibition similarly impaired filopodia formation in vitro and in developing zebrafish in vivo. During mouse retinal angiogenesis, CDC42 inhibition impaired tip cell and vascular network formation, causing defects that resembled those due to loss of ECM-induced, but not VEGF-induced, NRP1 signaling. We conclude that NRP1 enables ECM-induced filopodia formation for tip cell function during sprouting angiogenesis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Cell Reports
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    • "In addition, macrophages secrete matrix metalloproteinases Hallmarks of Resistance to Antiangiogenic Therapy (MMPs), which results in extracellular matrix degradation and release of matrix-sequestered growth factors that can promote angiogenesis and tumor growth (Bergers et al., 2000; Coussens and Werb, 2002; Huang et al., 2002; Mantovani et al., 2002). Macrophages also participate actively in vascular sprouting by functioning as "bridging cells" between two separate tip cells (Fantin et al., 2010; Schmidt and Carmeliet, 2010; Mantovani et al., 2013). From all this, it can be anticipated that macrophages can contribute to resistance to antiangiogenic therapy, but their exact role is still poorly understood. "
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    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.
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