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

Åsa Thulin, Maria Ringvall, Anna Dimberg, Karin Kårehed, Timo Väisänen, Marja Riitta Väisänen, Osama Hamad, Jian Wang, Rolf Bjerkvig, Bo Nilsson, Taina Pihlajaniemi, Helena Åkerud, Kristian Pietras, Wilhelm Jahnen-Dechent, Agneta Siegbahn, Anna Karin Olsson*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

33 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1792-1802
Number of pages11
JournalMolecular Cancer Research
Volume7
Issue number11
DOIs
Publication statusPublished - Nov 2009
Externally publishedYes

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