Activated Platelets Provide a Functional Microenvironment for the Antiangiogenic Fragment of Histidine-Rich Glycoprotein

The angiogenesis inhibitor histidine-rich glycoprotein (HRG) constitutes one of several examples of molecules regulating both angiogenesis and hemostasis. The antiangiogenic properties of HRG are mediated via its proteolytically released histidine- and proline-rich (His/Pro-rich) domain. Using a com...

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Bibliographic Details
Published in:	Molecular cancer research 2009-11, Vol.7 (11), p.1792-1802
Main Authors:	Thulin, Åsa, Ringvall, Maria, Dimberg, Anna, Kårehed, Karin, Väisänen, Timo, Väisänen, Marja-Riitta, Hamad, Osama, Wang, Jian, Bjerkvig, Rolf, Nilsson, Bo, Pihlajaniemi, Taina, Åkerud, Helena, Pietras, Kristian, Jahnen-Dechent, Wilhelm, Siegbahn, Agneta, Olsson, Anna-Karin
Format:	Article
Language:	eng
Subjects:	Amino Acid Sequence angiogenesis angiogenesis inhibitor Angiogenesis Inhibitors - metabolism Animals Blood Platelets - metabolism cancer Endothelial Cells - metabolism Female histidine-rich glycoprotein Humans Immunohistochemistry Male MEDICIN Medicin och hälsovetenskap MEDICINE Mice Mice, Inbred C57BL Mice, Transgenic Molecular Sequence Data Neoplasms - blood Neoplasms - blood supply Neoplasms - metabolism Neovascularization, Pathologic - blood Neovascularization, Pathologic - pathology Peptide Fragments - blood Peptide Fragments - metabolism platelet Platelet Activation platelets Proteins - metabolism proteolytic fragment Repetitive Sequences, Amino Acid
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Summary:	The angiogenesis inhibitor histidine-rich glycoprotein (HRG) constitutes one of several examples of molecules regulating both angiogenesis and hemostasis. The antiangiogenic properties of HRG are mediated via its proteolytically released histidine- and proline-rich (His/Pro-rich) domain. Using a combination of immunohistochemistry and mass spectrometry, we here provide biochemical evidence for the presence of a proteolytic peptide, corresponding to the antiangiogenic domain of HRG, in vivo in human tissue. This finding supports a role for HRG as an endogenous regulator of angiogenesis. Interestingly, the His/Pro-rich peptide bound to the vessel wall in tissue from cancer patients but not to the vasculature in tissue from healthy persons. Moreover, the His/Pro-rich peptide was found in close association with platelets. Relesate from in vitro –activated platelets promoted binding of the His/Pro-rich domain of HRG to endothelial cells, an effect mediated by Zn 2+ . Previous studies have shown that zinc-dependent binding of the His/Pro-rich domain of HRG to heparan sulfate on endothelial cells is required for inhibition of angiogenesis. We describe a novel mechanism to increase the local concentration and activity of an angiogenesis inhibitor, which may reflect a host response to counteract angiogenesis during pathologic conditions. Our finding that tumor angiogenesis is elevated in HRG-deficient mice supports this conclusion. (Mol Cancer Res 2009;7(11):1792–802)
ISSN:	1541-7786 1557-3125 1557-3125