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Thrombin receptor PAR-1 activation on endothelial progenitor cells enhances chemotaxis-associated genes expression and leukocyte recruitment by a COX-2-dependent mechanism

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Abstract

Background

Endothelial colony forming cells (ECFC) represent a subpopulation of endothelial progenitor cells involved in endothelial repair. The activation of procoagulant mechanisms associated with the vascular wall’s inflammatory responses to injury plays a crucial role in the induction and progression of atherosclerosis. However, little is known about ECFC proinflammatory potential.

Aims

To explore the role of the thrombin receptor PAR-1 proinflammatory effects on ECFC chemotaxis/recruitment capacity.

Methods and results

The expression of 30 genes known to be associated with inflammation and chemotaxis was quantified in ECFC by real-time qPCR. PAR-1 activation with the SFLLRN peptide (PAR-1-ap) resulted in a significant increase in nine chemotaxis-associated genes expression, including CCL2 and CCL3 whose receptors are present on ECFC. Furthermore, COX-2 expression was found to be dramatically up-regulated consequently to PAR-1 activation. COX-2 silencing with the specific COX-2-siRNA also triggered down-regulation of the nine target genes. Conditioned media (c.m.) from control-siRNA- and COX-2-siRNA-transfected ECFC, stimulated or not with PAR-1-ap, were produced and tested on ECFC capacity to recruit leukocytes in vitro as well in the muscle of ischemic hindlimb in a preclinical model. The capacity of the c.m. from ECFC stimulated with PAR-1-ap to recruit leukocytes was abrogated when COX-2 gene expression was silenced in vitro (in terms of U937 cells migration and adhesion to endothelial cells) as well as in vivo. Finally, the postnatal vasculogenic stem cell derived from infantile hemangioma tumor (HemSC) incubated with PAR-1-ap increased leukocyte recruitment in Matrigel® implant.

Conclusions

PAR-1 activation in ECFC increases chemotactic gene expression and leukocyte recruitment at ischemic sites through a COX-2-dependent mechanism.

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Acknowledgments

This project has been realized with grants obtain from the Conny-Maeva Charitable Foundation and from “Région Ile de France-CORDDIM” (Domaine d’intérêt majeur Cardiovasculaire Obésité Rein Diabète). Dr. Clement d’Audigier was supported by a grant from generous donators of the “Fondation pour la recherche médicale” (FRM). Dr. Elisa Rossi was supported by a grant from the generous donators of the Conny-Maeva Charitable Foundation. We thank Pr. Joyce Bischoff and Dr. Lan Huang (Vascular Biology Program and Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA) for helpful discussion and expertise in hemangioma stem cells. We thank Pr. Carmelo Bernabeu (Centro de Investigaciones Biológicas, Madrid, Spain) for providing us human U937 lineage. We thank the nursing services of “Hôpital des Instructions et des Armées de Bégin (Saint-Mandé, France)” for providing us cord blood. Umbilical cord bloods were collected from consenting mothers. The study was approved by local ethics committee of “Hôpital des Instructions et des Armées de Begin (France) (201008043234797)” and protocol conformed to ethical guidelines of Declaration of Helsinki.

Conflict of interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Sorbonne Paris Cité, Université Paris Descartes, Paris, France

    Clément d’Audigier, Clément Cochain, Elisa Rossi, Coralie L. Guérin, Ivan Bièche, Adeline Blandinières, Jean-Sébastien Silvestre, Pascale Gaussem & David M. Smadja

  2. INSERM UMR-S 1140, Faculté de Pharmacie de Paris, Paris, France

    Clément d’Audigier, Elisa Rossi, Adeline Blandinières, Bérengère Marsac, Pascale Gaussem & David M. Smadja

  3. AP-HP, Service d’Hématologie Biologique, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015, Paris, France

    Adeline Blandinières, Pascale Gaussem & David M. Smadja

  4. INSERM, UMR-S 970, Paris Cardiovascular Research Center - PARCC, Paris, France

    Clément Cochain, Coralie L. Guérin & Jean-Sébastien Silvestre

  5. INSERM UMR-S 745, Faculté de Pharmacie de Paris, Paris, France

    Ivan Bièche

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  1. Clément d’Audigier
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  2. Clément Cochain
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d’Audigier, C., Cochain, C., Rossi, E. et al. Thrombin receptor PAR-1 activation on endothelial progenitor cells enhances chemotaxis-associated genes expression and leukocyte recruitment by a COX-2-dependent mechanism. Angiogenesis 18, 347–359 (2015). https://doi.org/10.1007/s10456-015-9471-8

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