In Vitro and In Vivo Antiangiogenic Properties of the Serpin Protease Nexin-1

Author:

Selbonne Sonia1,Azibani Feriel1,Iatmanen Soria1,Boulaftali Yacine1,Richard Benjamin12,Jandrot-Perrus Martine1,Bouton Marie-Christine1,Arocas Véronique1

Affiliation:

1. INSERM and Université Paris Diderot, Sorbonne Paris Cité, Paris, France

2. Université Paris 13, Bobigny, France

Abstract

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.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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