Activated platelets provide a functional microenvironment for the antiangiogenic fragment of histidine-rich glycoprotein.

Abstract

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.

• Authors: Asa Thulin, Maria Ringvall, Anna Dimberg, Karin Kårehed, Timo Väisänen, Marja-Riitta Väisänen, Osama Hamad, Jian Wang, Rolf Bjerkvig, Bo Nilsson, Taina Pihlajaniemi, Helena Akerud, Kristian Pietras, Wilhelm Jahnen-Dechent, Agneta Siegbahn, Anna-Karin Olsson
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 7 Issue 11 Pg. 1792-802 (Nov 2009) ISSN: 1557-3125 [Electronic] United States
• PMID: 19903770 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Peptide Fragments
• Proteins
• histidine-rich proteins

Topics

• Amino Acid Sequence
• Angiogenesis Inhibitors (metabolism)
• Animals
• Blood Platelets (metabolism)
• Endothelial Cells (metabolism)
• Female
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Molecular Sequence Data
• Neoplasms (blood, blood supply, metabolism)
• Neovascularization, Pathologic (blood, pathology)
• Peptide Fragments (blood, metabolism)
• Platelet Activation
• Proteins (metabolism)
• Repetitive Sequences, Amino Acid