Proteolytic exposure of a cryptic site within collagen type IV is requiredfor angiogenesis and tumor growth in vivo

Evidence is provided that proteolytic cleavage of collagen type IV results in the exposure of a functionally important cryptic site hidden within its triple helical structure. Exposure of this cryptic site was associated with angiogenic, but not quiescent, blood vessels and was required for angiogen esis in vivo. Exposure of the HUIV26 epitope was associated with a loss of alpha1 beta1 integrin binding and the gain of alphav beta3 binding. A monoc lonal antibody (HUIV26) directed to this site disrupts integrin-dependent e ndothelial cell interactions and potently inhibits angiogenesis and tumor g rowth. Together, these studies suggest a novel mechanism by which proteolys is contributes to angiogenesis by exposing hidden regulatory elements withi n matrix-immobilized collagen type IV.