mCRP triggers angiogenesis by inducing F3 transcription and TF signalling in microvascular endothelial cells

Esther Peña; Raquel de la Torre; Gemma Arderiu; Mark Slevin; Lina Badimon

doi:10.1160/TH16-07-0524

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2017; 117(02): 357-370
DOI: 10.1160/TH16-07-0524

Endothelium and Angiogenesis

Schattauer GmbH

mCRP triggers angiogenesis by inducing F3 transcription and TF signalling in microvascular endothelial cells

Esther Peña

¹Cardiovascular Research Center (CSIC-ICCC), Institut Investigacions Biomèdiques Sant Pau (IIB-Sant Pau)

,

Raquel de la Torre

¹Cardiovascular Research Center (CSIC-ICCC), Institut Investigacions Biomèdiques Sant Pau (IIB-Sant Pau)

,

Gemma Arderiu

¹Cardiovascular Research Center (CSIC-ICCC), Institut Investigacions Biomèdiques Sant Pau (IIB-Sant Pau)

,

Mark Slevin

²School of Healthcare Science, Manchester Metropolitan University, Manchester, UK

,

Lina Badimon

¹Cardiovascular Research Center (CSIC-ICCC), Institut Investigacions Biomèdiques Sant Pau (IIB-Sant Pau)

³Cardiovascular Research Chair-Foundation Jesus Serra, UAB, Barcelona, Spain

› Author Affiliations

Abstract

Summary

Inflammation contributes to vascular disease progression. However, the role of circulating inflammatory molecules on microvascular endothelial cell (mECs) is not fully elucidated. The aim of this study was to investigate the effects of the short pentraxin CRP on microvascular endothelial cell angiogenic function. Subcutaneously implanted collagen plugs seeded with human mECs exposed to monomeric CRP (mCRP) in mice showed formation of an extended network of microvessels both in the plug and the overlying skin tissue, while mECs exposure to pentameric native CRP (nCRP) induced a much milder effect. To understand the mechanisms behind this angiogenic effects, mECs were exposed to both CRP forms and cell migration, wound repair and tube-like formation were investigated. nCRP effects were moderate and of slow-onset whereas mCRP induced rapid, and highly significant effects. We investigated how circulating nCRP is transformed into mCRP by confocal microscopy and western blot. nCRP is transformed into mCRP on the mECs membranes in a time dependent fashion. This transformation is specific and in part receptor dependent, and the formed mCRP triggers F3 gene transcription and TF-protein expression in mECs to induce angiogenesis. F3-silenced mECs are unable to form angiotubes. In agreement, mCRP induced upregulation of the TF signalling pathway in mECs with downstream phosphorylation of AKT and activation of the transcription factor ETS1 leading to increased CCL2 release. The circulating pentraxin nCRP with little pro-angiogenic effect when dissociated into mCRP on the surface of mECs is able to trigger potent proangiogenic effects by inducing F3-gene upregulation and TF signalling.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Tissue factor - angiogenesis - vessel wall remodelling - C-reactive protein - endothelial cells

Full Text

References

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