title: In vitro and in vivo antiangiogenic properties of the serpin protease nexin-1.
abstract: The serpin protease nexin-1 (PN-1) is expressed by vascular cells and secreted by platelets upon activation, and it is known to interact with several modulators of angiogenesis, such as proteases, matrix proteins, and glycosaminoglycans. We therefore investigated the impact of PN-1 on endothelial cell angiogenic responses in vitro and ex vivo and in vivo in PN-1-deficient mice. We found that PN-1 is antiangiogenic in vitro: it inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell responses, including proliferation, migration, and capillary tube formation, and decreased cell spreading on vitronectin. These effects do not require the antiprotease activity of PN-1 but involve PN-1 binding to glycosaminoglycans. In addition, our results indicated that PN-1 does not act by blocking VEGF binding to its heparan sulfate proteoglycan coreceptors. The results obtained in vitro were supported ex vivo in PN-1-deficient mice, where the microvascular network sprouting from aortic rings was significantly enhanced. Moreover, in vivo, neovessel formation was promoted in the Matrigel plug assay in PN-1-deficient mice compared to wild-type mice, and these effects were reversed by the addition of recombinant PN-1. Taken together, our results demonstrate that PN-1 has direct antiangiogenic properties and is a yet-unrecognized player in the angiogenic balance.
authors.affiliation: INSERM and Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Selbonne
authors.forename: Feriel
authors.initials: F
authors.lastname: Azibani
authors.forename: Soria
authors.initials: S
authors.lastname: Iatmanen
authors.forename: Yacine
authors.initials: Y
authors.lastname: Boulaftali
authors.forename: Benjamin
authors.initials: B
authors.lastname: Richard
authors.forename: Martine
authors.initials: M
authors.lastname: Jandrot-Perrus
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Bouton
authors.forename: Véronique
authors.initials: V
authors.lastname: Arocas
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; C545486:SERPINE2 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D042461:Vascular Endothelial Growth Factor A