mCRP triggers angiogenesis by inducing F3 transcription and TF signalling in microvascular endothelial cells.
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.
Esther
E
Peña
Raquel
R
de la Torre
Gemma
G
Arderiu
Mark
M
Slevin
Prof. Lina Badimon, Cardiovascular Research Center, Hospital de la Santa Creu i Sant Pau, C/ Sant Antoni Mª Claret 167, 08025 Barcelona, Spain, Tel.: +34 93 556 58 80, Fax: +34 93 556 55 59, E-mail: lbadimon@csic-iccc.org.
Lina
L
Badimon
D043925:Angiogenesis Inducing Agents / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002097:C-Reactive Protein / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation; D006801:Humans; D008819:Mice, Nude; D055806:Microvessels / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects*
D043925:Angiogenesis Inducing Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C494041:ETS1 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D002097:C-Reactive Protein; D013925:Thromboplastin; D051057:Proto-Oncogene Proteins c-akt
C-reactive protein; Tissue factor; angiogenesis; endothelial cells; vessel wall remodelling