Faculty Collaboration Database

Histidine-rich glycoprotein modulates the anti-angiogenic effects of vasculostatin. Am J Pathol 2010 Apr;176(4):2039-50

Date

02/20/2010

Pubmed ID

20167858

Pubmed Central ID

PMC2843491

DOI

10.2353/ajpath.2010.090782

Scopus ID

2-s2.0-77950574193 (requires institutional sign-in at Scopus site)   44 Citations

Abstract

Brain angiogenesis inhibitor 1 (BAI1) is a transmembrane protein expressed on glial cells within the brain. Its expression is dramatically down-regulated in many glioblastomas, consistent with its functional ability to inhibit angiogenesis and tumor growth in vivo. We have shown that the soluble anti-angiogenic domain of BAI1 (termed Vstat120) requires CD36, a cell surface glycoprotein expressed on microvascular endothelial cells (MVECs), for it to elicit an anti-angiogenic response. We now report that Vstat120 binding to CD36 on MVECs activates a caspase-mediated pro-apoptotic pathway, and this effect is abrogated by histidine-rich glycoprotein (HRGP). HRGP is a circulating glycoprotein previously shown to function as a CD36 decoy to promote angiogenesis in the presence of thrombospondin-1 or -2. Data here show that Vstat120 specifically binds HRGP. Under favorable MVEC growth conditions this interaction allows chemotactic-directed migration as well as endothelial tube formation to persist in in vitro cellular systems, and increased tumor growth in vivo as demonstrated in both subcutaneous and orthotopic brain tumor models, concomitant with an increase in tumor vascularity. Finally, we show that HRGP expression is increased in human brain cancers, with the protein heavily localized to the basement membrane of the tumors. These data help define a novel angiogenic axis that could be exploited for the treatment of human cancers and other diseases where excess angiogenesis occurs.

Author List

Klenotic PA, Huang P, Palomo J, Kaur B, Van Meir EG, Vogelbaum MA, Febbraio M, Gladson CL, Silverstein RL

Author

Roy L. Silverstein MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiogenesis Inhibitors
Angiogenic Proteins
Animals
Brain
CD36 Antigens
Cell Line, Tumor
Cell Movement
Gene Expression Regulation, Neoplastic
Glioma
Glycoproteins
Humans
Male
Mice
Mice, Nude
Neoplasms
Neovascularization, Pathologic
Peptide Fragments
Receptors, G-Protein-Coupled
Recombinant Fusion Proteins
Wound Healing