title: Regulatory effects of ferritin on angiogenesis.
abstract: Angiogenesis, the synthesis of new blood vessels from preexisting vessels, plays a critical role in normal wound healing and tumor growth. HKa (cleaved high molecular weight kininogen) is an endogenous inhibitor of angiogenesis formed by the cleavage of kininogen on endothelial cells. Ferritin is a protein principally known for its central role in iron storage. Here, we demonstrate that ferritin binds to HKa with high affinity (K(d) 13 nM). Further, ferritin antagonizes the antiangiogenic effects of HKa, enhancing the migration, assembly, and survival of HKa-treated endothelial cells. Effects of ferritin were independent of its iron content. Peptide mapping revealed that ferritin binds to a 22-aa subdomain of HKa that is critical to its antiangiogenic activity. In vivo, ferritin opposed HKa's antiangiogenic effects in a human prostate cancer xenograft, restoring tumor-dependent vessel growth. Ferritin-mediated regulation of angiogenesis represents a new angiogenic regulatory pathway, and identifies a new role for ferritin in cell biology.
authors.affiliation: Program in Molecular Medicine, Wake Forest University School of Medicine, Winston Salem NC 27157, USA.
authors.forename: Lan G
authors.initials: LG
authors.lastname: Coffman
authors.forename: Derek
authors.initials: D
authors.lastname: Parsonage
authors.forename: Ralph
authors.initials: R
authors.lastname: D'Agostino
authors.forename: Frank M
authors.initials: FM
authors.lastname: Torti
authors.forename: Suzy V
authors.initials: SV
authors.lastname: Torti
mesh_terms: D002465:Cell Movement; D042783:Endothelial Cells / Q000502:physiology; D005293:Ferritins / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D019679:Kininogen, High-Molecular-Weight / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D009389:Neovascularization, Pathologic; D011471:Prostatic Neoplasms / Q000473:pathology; D011485:Protein Binding; D025941:Protein Interaction Mapping
chemical_list: D019679:Kininogen, High-Molecular-Weight; D005293:Ferritins