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Signal transduction in endothelial cells by the angiogenesis inhibitor histidine-rich glycoprotein targets focal adhesions
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Koagulation)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2006 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 312, no 13, 2547-2556 p.Article in journal (Refereed) Published
Abstract [en]

Histidine-rich glycoprotein (HRGP) is an abundant heparin-binding plasma protein. We have shown that a fragment released from the central histidine/proline-rich (His/Pro-rich) domain of HRGP blocks endothelial cell migration in vitro and vascularization and growth of murine fibrosarcoma in vivo. The minimal active HRGP domain exerting the anti-angiogenic effect was recently narrowed down to a 35 amino acid peptide, HRGP330, derived from the His/Pro-rich domain of HRGP. By use of a signal transduction antibody array representing 400 different signal transduction molecules, we now show that HRGP and the synthetic peptide HRGP330 specifically induce tyrosine phosphorylation of focal adhesion kinase and its downstream substrate paxillin in endothelial cells. HRGP/HRGP330 treatment of endothelial cells induced disruption of actin stress fibers, a process reversed by treatment of cells with the FAK inhibitor geldanamycin. In addition, VEGF-mediated endothelial cell tubular morphogenesis in a three-dimensional collagen matrix was inhibited by HRGP and HRGP330. In contrast, VEGF-induced proliferation was not affected by HRGP or HRGP330, demonstrating the central role of cell migration during tube formation. In conclusion, our data show that HRGP targets focal adhesions in endothelial cells, thereby disrupting the cytoskeletal organization and the ability of endothelial cells to assemble into vessel structures.

Place, publisher, year, edition, pages
2006. Vol. 312, no 13, 2547-2556 p.
Keyword [en]
Actins/metabolism, Angiogenesis Inhibitors/*pharmacology, Animals, Benzoquinones, Cattle, Cell Proliferation/drug effects, Cells; Cultured, Endothelial Cells/*cytology/*drug effects, Focal Adhesion Protein-Tyrosine Kinases/metabolism, Focal Adhesions/*drug effects, Humans, Lactams; Macrocyclic, Mice, Peptides/pharmacology, Phosphoproteins/metabolism, Phosphorylation/drug effects, Phosphotyrosine/metabolism, Protein Array Analysis, Proteins/*pharmacology, Quinones/pharmacology, Signal Transduction/*drug effects, Stress Fibers/drug effects, Vascular Endothelial Growth Factor A/pharmacology
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-12804DOI: 10.1016/j.yexcr.2006.04.022PubMedID: 16769050OAI: oai:DiVA.org:uu-12804DiVA: diva2:40573
Available from: 2008-01-15 Created: 2008-01-15 Last updated: 2017-12-11Bibliographically approved
In thesis
1. The Role of Histidine-rich Glycoprotein in Angiogenesis and Tumor Growth
Open this publication in new window or tab >>The Role of Histidine-rich Glycoprotein in Angiogenesis and Tumor Growth
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Histidine-rich glycoprotein (HRG) is a heparin-binding plasma protein modulating immune, hemostatic and vascular functions. I have studied the antiangiogenic functions of HRG in vitro and in vivo in order to understand the molecular mechanisms of action of HRG as an angiogenesis inhibitor.

Angiogenesis is the formation of new blood vessels from the pre-existing vasculature. It is a central rate-limiting step of tumor development and thus a possible target for cancer therapeutics. Previous studies have shown that HRG has antiangiogenic functions in vivo and that the antiangiogenic effects are mediated via the proteolytically released His/Pro-rich domain of HRG. In this thesis we demonstrate that HRG can inhibit endothelial cell migration by interfering with focal adhesion and cytoskeletal turnover. Moreover we have identified the minimal active domain of HRG, a 35 amino acid peptide derived from the histidine- and proline-rich domain of HRG.

Analyzing human tumor tissue samples, we have found that a His/Pro-rich fragment of HRG is bound to the vasculature from cancer patients but not to the vasculature from healthy individuals. The fragment is found in association with platelets, and we show that activated platelets can induce a functional microenvironment for the His/Pro-rich fragment. Cancer patients often display an increased coagulation and our data describe a new mechanism to confer specificity of an angiogenesis inhibitor for situations with enhanced platelet activation, as in the tumor.

We have further studied the role of HRG in tumor growth by crossing HRG-deficient mice with a transgenic mouse model of pancreatic insulinoma. We show that mice lacking HRG display an elevated “angiogenic switch” and that the total tumor volume is larger in these mice than in wild type mice. HRG is also involved in regulation of platelet function and platelets can stimulate angiogenesis in various ways. We have depleted mice of platelets to study the possible connection between the function of HRG in angiogenesis and platelet regulation. Our data suggest an involvement of platelets in the antiangiogenic activities of HRG.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 505
Keyword
Histidine-rich glycoprotein, HRG/HRGP/HPRG, angiogenesis inhibitor, cancer, VEGF, platelets
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:uu:diva-110829 (URN)978-91-554-7674-8 (ISBN)
Public defence
2010-01-16, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Available from: 2009-12-22 Created: 2009-11-26 Last updated: 2011-02-28Bibliographically approved

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Thulin, ÅsaClaesson-Welsh, LenaOlsson, Anna-Karin

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