title: Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation.
abstract: Angiostatin effectively blocks tumor angiogenesis through still poorly understood mechanisms. Given the close association between immune and vascular regulation, we investigated the effects of angiostatin on angiogenesis-associated leukocytes. Angiostatin inhibited the migration of monocytes and, even more markedly, neutrophils. Angiostatin blocked chemotaxis of neutrophils to CXCR2 chemokine receptor agonists (IL-8, MIP-2, and GROalpha), formyl-Met-Leu-Phe (fMLP), and 12-O-tetradecanoylphorbol 13-acetate, and repressed fMLP-induced mitochondrial activity. Two different angiostatin forms (kringles 1-4 and 1-3) were effective, whereas whole plasminogen had no effect. IL-8, MIP-2, and GROalpha induced intense angiogenic reactions in vivo, but no angiogenic response to these factors was observed in neutropenic mice, demonstrating an essential role for neutrophils. Angiostatin potently inhibited chemokine-induced angiogenesis in vivo, and consistent with in vitro observations, both angiostatin forms were active and whole plasminogen had little effect. Angiostatin inhibition of angiogenesis in vivo was accompanied by a striking reduction in the number of recruited leukocytes. In vivo, the inflammatory agent lipopolysaccharide also induced extensive leukocyte infiltration and angiogenesis that were blocked by angiostatin. Neutrophils expressed mRNAs for ATP synthase and angiomotin, two known angiostatin receptors. These data show that angiostatin directly inhibits neutrophil migration and neutrophil-mediated angiogenesis and indicate that angiostatin might inhibit inflammation.
authors.affiliation: Centro di Biotecnologie Avanzate, 16132 Genova, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Benelli
authors.forename: Monica
authors.initials: M
authors.lastname: Morini
authors.forename: Fabio
authors.initials: F
authors.lastname: Carrozzino
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Ferrari
authors.forename: Simona
authors.initials: S
authors.lastname: Minghelli
authors.forename: Leonardo
authors.initials: L
authors.lastname: Santi
authors.forename: Marco
authors.initials: M
authors.lastname: Cassatella
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Noonan
authors.forename: Adriana
authors.initials: A
authors.lastname: Albini
mesh_terms: D043168:Angiostatins; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000517:prevention & control; D016209:Interleukin-8 / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010958:Plasminogen / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism
chemical_list: D016209:Interleukin-8; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D023063:Receptors, Interleukin-8B; D043168:Angiostatins; D010958:Plasminogen