title: C-reactive protein exerts angiogenic effects on vascular endothelial cells and modulates associated signalling pathways and gene expression.
abstract: BACKGROUND
  Formation of haemorrhagic neovessels in the intima of developing atherosclerotic plaques is thought to significantly contribute to plaque instability resulting in thrombosis. C-reactive protein (CRP) is an acute phase reactant whose expression in the vascular wall, in particular, in reactive plaque regions, and circulating levels increase in patients at high risk of cardiovascular events. Although CRP is known to induce a pro-inflammatory phenotype in endothelial cells (EC) a direct role on modulation of angiogenesis has not been established.
  
  
  RESULTS
  Here, we show that CRP is a powerful inducer of angiogenesis in bovine aortic EC (BAEC) and human coronary artery EC (HCAEC). CRP, at concentrations corresponding to moderate/high risk (1-5 microg/ml), induced a significant increase in proliferation, migration and tube-like structure formation in vitro and stimulated blood vessel formation in the chick chorioallantoic membrane assay (CAM). CRP treated with detoxi-gel columns retained such effects. Western blotting showed that CRP increased activation of early response kinase-1/2 (ERK1/2), a key protein involved in EC mitogenesis. Furthermore, using TaqMan Low-density Arrays we identified key pro-angiogenic genes induced by CRP among them were vascular endothelial cell growth factor receptor-2 (VEGFR2/KDR), platelet-derived growth factor (PDGF-BB), notch family transcription factors (Notch1 and Notch3), cysteine-rich angiogenic inducer 61 (CYR61/CCN1) and inhibitor of DNA binding/differentiation-1 (ID1).
  
  
  CONCLUSIONS
  This data suggests a role for CRP in direct stimulation of angiogenesis and therefore may be a mediator of neovessel formation in the intima of vulnerable plaques.
authors.affiliation: Department of Neurology, University Hospital of Bellvitge, Fundació IDIBELL, Barcelona, Spain. marta.miguel@gmail.com
authors.forename: Marta M
authors.initials: MM
authors.lastname: Turu
authors.forename: Mark
authors.initials: M
authors.lastname: Slevin
authors.forename: Sabine
authors.initials: S
authors.lastname: Matou
authors.forename: David
authors.initials: D
authors.lastname: West
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez
authors.forename: Ana
authors.initials: A
authors.lastname: Luque
authors.forename: Marta
authors.initials: M
authors.lastname: Grau-Olivares
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
authors.forename: Jose
authors.initials: J
authors.lastname: Martinez-Gonzalez
authors.forename: Jerzy
authors.initials: J
authors.lastname: Krupinski