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

Mol Cancer Res. 2009 Nov;7(11):1792-802. doi: 10.1158/1541-7786.MCR-09-0094. Epub 2009 Nov 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Neoplasms / blood supply*
  • Neoplasms / metabolism*
  • Neovascularization, Pathologic / blood
  • Neovascularization, Pathologic / pathology
  • Peptide Fragments / blood
  • Peptide Fragments / metabolism
  • Platelet Activation
  • Proteins / metabolism*
  • Repetitive Sequences, Amino Acid

Substances

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