Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1
Ronit Simantov, … , Ralph L. Nachman, Roy L. Silverstein
Ronit Simantov, … , Ralph L. Nachman, Roy L. Silverstein
Published January 1, 2001
Citation Information: J Clin Invest. 2001;107(1):45-52. https://doi.org/10.1172/JCI9061.
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Article

Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1

Abstract

Angiogenesis is critical for the growth and proliferation of tumors as well as for normal development. We now describe a novel role for histidine-rich glycoprotein (HRGP) in the modulation of angiogenesis. HRGP is a plasma protein that circulates in relatively high concentrations (1.5 μM), but has no known function in vivo. We have shown previously that HRGP binds with high affinity to thrombospondin-1 (TSP-1), a homotrimeric glycoprotein that is a potent inhibitor of angiogenesis. The antiangiogenic activity of TSP-1 is mediated by the binding of properdin-like type I repeats to the receptor CD36. We found that binding of HRGP to TSP-1 was similarly mediated by TSP type I repeats. HRGP colocalized with TSP-1 in the stroma of human breast cancer specimens, and this interaction masked the antiangiogenic epitope of TSP-1. In assays performed in vitro of endothelial cell migration and tube formation, and in vivo corneal angiogenesis assays, HRGP inhibited the antiangiogenic effect of TSP-1. These studies suggest that HRGP can modulate the antiangiogenic activity of TSP-1, and identify a potential mechanism of resistance to the antiangiogenic effect of TSP-1.

Authors

Ronit Simantov, Maria Febbraio, René Crombie, Adam S. Asch, Ralph L. Nachman, Roy L. Silverstein

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Figure 1

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The type 1 repeat of TSP mediates binding to HRGP. Peptides derived from...
The type 1 repeat of TSP mediates binding to HRGP. Peptides derived from the multiple domains of TSP-1 are shown. Mutated amino acids are italicized and type I repeat–derived peptides are in boldface. HRGP (1 μg/ml) binding to TSP-1 immobilized on plastic wells was measured by enzyme-linked immunosorbent assay (ELISA) using an alkaline phosphatase–conjugated anti-HRGP Ab and p-nitrophenyl phosphate substrate. HRGP binding in the presence of TSP-1 peptides is expressed as percent binding in the absence of peptide.