Angiostatic peptides use plasma fibronectin to home to angiogenic vasculature.
A group of angiogenesis inhibitors are derived from fragments of extracellular matrix or blood proteins. Endostatin, antithrombin, and anastellin are members of this group of substances. The plasma adhesion proteins fibronectin and vitronectin serve as cofactors for these three antiangiogenic proteins. Anginex is a synthetic 33-amino acid peptide that was originally modeled to reproduce the beta-sheet structure of antiangiogenic proteins. Here, we show that anginex initiates fibronectin polymerization and is inactive in mice that lack plasma fibronectin. Anginex shares these characteristics with anastellin. Fluorescein-labeled anginex and anastellin specifically localized in angiogenic vessels in vivo. This localization was dependent on plasma fibronectin and inhibited by an Arg-Gly-Asp peptide. Thus, anginex shares with several physiological angiogenesis inhibitors a dependence on plasma adhesion proteins. The role of the adhesion protein interaction apparently is to form integrin-binding complexes that deliver the antiangiogenic proteins to sites of angiogenesis. This functional convergence of several antiangiogenic factors has important implications for antiangiogenic therapies.
Akerman
Maria E
ME
Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Pilch
Jan
J
Peters
David
D
Ruoslahti
Erkki
E
D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D043165:Angiostatic Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001672:Biocompatible Materials / Q000378:metabolism; D001808:Blood Vessels / Q000033:anatomy & histology / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D009842:Oligopeptides / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides; D010949:Plasma / Q000737:chemistry; D011108:Polymers / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D019096:Vitronectin / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D043165:Angiostatic Proteins; D001672:Biocompatible Materials; D004338:Drug Combinations; D005353:Fibronectins; D007797:Laminin; D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; D011108:Polymers; D011506:Proteins; D011509:Proteoglycans; D019096:Vitronectin; C423921:anastellin; C111993:betapep-25 protein, synthetic; C059485:matrigel; C047981:arginyl-glycyl-aspartic acid; D003094:Collagen