TY - JOUR
T1 - Activated platelets provide a functional microenvironment for the antiangiogenic fragment of histidine-rich glycoprotein
AU - Thulin, Åsa
AU - Ringvall, Maria
AU - Dimberg, Anna
AU - Kårehed, Karin
AU - Väisänen, Timo
AU - Väisänen, Marja Riitta
AU - Hamad, Osama
AU - Wang, Jian
AU - Bjerkvig, Rolf
AU - Nilsson, Bo
AU - Pihlajaniemi, Taina
AU - Åkerud, Helena
AU - Pietras, Kristian
AU - Jahnen-Dechent, Wilhelm
AU - Siegbahn, Agneta
AU - Olsson, Anna Karin
PY - 2009/11
Y1 - 2009/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=72449134912&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-09-0094
DO - 10.1158/1541-7786.MCR-09-0094
M3 - Article
C2 - 19903770
AN - SCOPUS:72449134912
SN - 1541-7786
VL - 7
SP - 1792
EP - 1802
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 11
ER -