Activated platelets provide a functional microenvironment for the antiangiogenic fragment of histidine-rich glycoprotein
2009 (English)In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 7, no 11, 1792-1802 p.Article in journal (Refereed) Published
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 massspectrometry, we here provide biochemical evidence for thepresence 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 Zn2+.Previous studies have shown that zinc-dependent bindingof 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.
Place, publisher, year, edition, pages
2009. Vol. 7, no 11, 1792-1802 p.
histidine-rich glycoprotein, angiogenesis, cancer, platelets
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-110827DOI: 10.1158/1541-7786.MCR-09-0094ISI: 000272006300005PubMedID: 19903770OAI: oai:DiVA.org:uu-110827DiVA: diva2:278488