title: Granzyme B cleavage of fibronectin disrupts endothelial cell adhesion, migration and capillary tube formation.
abstract: Dysregulated angiogenesis contributes to the pathogenesis of chronic inflammatory diseases. Modulation of the extracellular matrix by immune-derived proteases can alter endothelial cell-matrix interactions as well as endothelial cell sprouting, migration and capillary formation. Granzyme B is a serine protease that is expressed by a variety of immune cells, and accumulates in the extracellular milieu in many chronic inflammatory disorders that are associated with dysregulated angiogenesis. Although granzyme B is known to cleave fibronectin, an essential glycoprotein in vascular morphogenesis, the role of granzyme B in modulating angiogenesis is unknown. In the present study, granzyme B cleaved both plasma fibronectin and cell-derived fibronectin, resulting in the release of multiple fibronectin fragments. Granzyme B cleavage of fibronectin resulted in a dose-dependent reduction in endothelial cell adhesion to fibronectin as well as reduced endothelial cell migration and tubular formation. These events were prevented when granzyme B activity was inhibited by a small molecule inhibitor. In summary, granzyme B-mediated cleavage of fibronectin contributes to attenuated angiogenesis through the disruption of endothelial cell - fibronectin interaction resulting in impaired endothelial cell migration and tubular formation.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. alon.hendel@hli.ubc.ca
authors.forename: Alon
authors.initials: A
authors.lastname: Hendel
authors.forename: David J
authors.initials: DJ
authors.lastname: Granville
mesh_terms: D000704:Analysis of Variance; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism*; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008856:Microscopy, Fluorescence; D018919:Neovascularization, Physiologic / Q000502:physiology*
chemical_list: D005353:Fibronectins; D053804:Granzymes