mCRP triggers angiogenesis by inducing F3 transcription and TF signalling in microvascular endothelial cellsFinancial support: This work was supported by Spanish Ministry of Science Plan Estatal I+D+I 2013–2016 [SAF2013–42962-R to LB] cofunded by Fondo Europeo de Desarrollo Regional (FEDER-“Una manera de hacer Europa”), Red de Terapia Celular [RD/12/0019/0026 to LB] and Red Investigación Cardiovascular [RD/12/00420027 to LB] (CPII13/00012, PI12/02332 to GA) from Instituto Salud Carlos III (ISCIII), Fundación de Investigación Cardiovascular and Fundación Jesus Serra. GA is a Miguel Servet investigator from the Instituto de Salud Carlos III.
Received:11 July 2016
Accepted after major revision:16 October 2016
01 December 2017 (online)
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.
KeywordsTissue factor - angiogenesis - vessel wall remodelling - C-reactive protein - endothelial cells
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