title: 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.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala Biomedical Center, Uppsala, Sweden.
authors.forename: Asa
authors.initials: A
authors.lastname: Thulin
authors.forename: Maria
authors.initials: M
authors.lastname: Ringvall
authors.forename: Anna
authors.initials: A
authors.lastname: Dimberg
authors.forename: Karin
authors.initials: K
authors.lastname: Kårehed
authors.forename: Timo
authors.initials: T
authors.lastname: Väisänen
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Väisänen
authors.forename: Osama
authors.initials: O
authors.lastname: Hamad
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.forename: Bo
authors.initials: B
authors.lastname: Nilsson
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
authors.forename: Helena
authors.initials: H
authors.lastname: Akerud
authors.forename: Kristian
authors.initials: K
authors.lastname: Pietras
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Jahnen-Dechent
authors.forename: Agneta
authors.initials: A
authors.lastname: Siegbahn
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Olsson
mesh_terms: D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000097:blood / Q000098:blood supply* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000097:blood / Q000473:pathology; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism; D015539:Platelet Activation; D011506:Proteins / Q000378:metabolism*; D020449:Repetitive Sequences, Amino Acid; D000099053:Histidine-Rich Glycoprotein
chemical_list: D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D011506:Proteins; D000099053:Histidine-Rich Glycoprotein