Activated platelets provide a functional microenvironment for the antiangiogenic fragment of histidine-rich glycoprotein.
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.
Thulin
Asa
A
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala Biomedical Center, Uppsala, Sweden.
Ringvall
Maria
M
Dimberg
Anna
A
Kårehed
Karin
K
Väisänen
Timo
T
Väisänen
Marja-Riitta
MR
Hamad
Osama
O
Wang
Jian
J
Bjerkvig
Rolf
R
Nilsson
Bo
B
Pihlajaniemi
Taina
T
Akerud
Helena
H
Pietras
Kristian
K
Jahnen-Dechent
Wilhelm
W
Siegbahn
Agneta
A
Olsson
Anna-Karin
AK
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
D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D011506:Proteins; D000099053:Histidine-Rich Glycoprotein