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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4542-4550. Prepublished online as a Blood First Edition Paper on February 21, 2008; DOI 10.1182/blood-2007-06-094763. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-06-094763v1 111/9/4542    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Fens, M. H. A. M. Articles by Schiffelers, R. M. PubMed PubMed Citation Articles by Fens, M. H. A. M. Articles by Schiffelers, R. M. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Angiogenic endothelium shows lactadherin-dependent phagocytosis of aged erythrocytes and apoptotic cells Marcel H. A. M. Fens1, Enrico Mastrobattista1, Anko M. de Graaff2, Frits M. Flesch1, Anton Ultee3, Jan T. Rasmussen4, Grietje Molema5, Gert Storm1, and Raymond M. Schiffelers1 1 Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands; 2 Department of Biochemistry and Cell Biology, and 3 Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands; 4 Protein Chemistry Laboratory, Department of Molecular Biology, Aarhus University, Aarhus, Denmark; and 5 Department of Pathology and Laboratory Medicine, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Angiogenic endothelium plays a crucial role in tumor growth. During angiogenesis, complex alterations in the microenvironment occur. In response, the endothelium undergoes phenotypic changes, for example overexpression of v-integrins. Here, we show that the overexpression of v-integrins on angiogenic endothelial cells is engaged in phagocytic actions involving binding ("tethering") and uptake ("tickling") of lactadherin (also termed MFG-E8)–opsonized particles. Phosphatidylserine (PS)–exposing multilamellar vesicles, "aged" erythrocytes, and apoptotic melanoma cells incubated with lactadherin were all phagocytosed by angiogenic endothelial cells in vitro. Furthermore, we demonstrated lactadherin expression in and around tumor blood vessels making opsonization in situ plausible. By engineering the surface of erythrocytes with covalently coupled cyclic Arg-Gly-Asp (RGD) peptides—mimicking lactadherin opsonization—we could induce phagocytosis by angiogenic endothelial cells both in vitro and in vivo. In vitro, this was confirmed by cytochalasin D preincubation. When RGD-erythrocytes were administered intravenously in tumor-bearing mice, blood vessel congestion followed by tumor core necrosis was seen. Moreover, RGD-erythrocytes could delay tumor growth in a murine melanoma model, possibly through induction of tumor infarctions. These results reveal that angiogenic endothelial cells have phagocytic properties for lactadherin-opsonized large particles and apoptotic cells. Implications of our findings for diagnostic and therapy of angiogenesis-driven diseases are discussed. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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