Common Angiogenic Signaling Pathways Induced by Monomeric C - reactive protein and FGF-2 through MAPK and PI3K

Abstract

Excessive angiogenesis (i.e. neovascularization) in atherosclerotic lesions, sites of dissociation of the inflammatory biomarker pentameric C-reactive protein (pCRP) into monomeric CRP (mCRP), represents a focus of plaque instability with haemorrhagic complications. We previously demonstrated mCRP pro-angiogenic effects on cultured aortic endothelial cells. However, mCRP effects in combination with FGF-2, pro-angiogenic factor released by activated macrophages infiltrating developing lesions, have not yet been described. Here, we examined in vitro the angiogenic capabilities of mCRP combined with FGF-2 by performing endothelial cell proliferation, migration, and differentiation including tube formation and spheroid sprouting assays. The signaling pathways were also investigated by Western blotting and all the cell-based assays were used with or without pharmacological inhibitors of mitogen-activated protein kinase (MAPK), phosphatidylinositol-3 kinase (PI3K) and γ-secretase, considered as key regulators of angiogenesis. We showed that mCRP-induced endothelial cell proliferation and migration required activation of PI3K pathway. MAPK pathway was essential in mCRP-induced endothelial cell proliferation and spheroid sprouting while γ-secretase activity was indispensable for mCRP-induced tube formation only. MAPK pathway was required in all FGF-2-stimulated angiogenic assays whereas γ-secretase slightly inhibited FGF-2 angiogenic effects. PI3K pathway was necessary for FGF-2 angiogenic activities except for cell differentiation. In most of the assays, the additive pro-angiogenic effects of mCRP combined to FGF-2 were mainly attenuated by PI3K and MAPK inhibitors. Altogether, mCRP and FGF-2 have common angiogenic signaling pathways through PI3K and MAPK. Thus, the therapeutic use of PI3K and MAPK inhibitors may inhibit this increased vascularization whilst reducing the haemorrhagic complications from unstable plaques.

Bioinformatics prediction and analysis of hub genes and pathways of three types of gynecological cancer

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C-reactive protein in gallbladder diseases: diagnostic and therapeutic insights

“…As lipid raft microdomains are implicated in various receptor medicated cell activation processes involving signaling pathways and nuclear transcription factors (Cheng and Smith 2019), a mechanism by which CRP may regulate inflammation is becoming apparent. Indeed, mCRP has been shown to stimulate intracellular signaling pathways that lead to transcription of pro-inflammatory genes that control the production of the neutrophil chemotactic factor and Interleukin 8 (IL-8), factors known to amplify the acute inflammatory response (Boras et al 2014(Boras et al , 2017Khreiss et al 2002Khreiss et al , 2004aKhreiss et al , b, 2005. mCRP binding to lipids is also relevant to lipoproteins metabolism as mCRP has been shown to affects the uptake of low-density lipoproteins (LDLs) by endothelial cells and macrophages (Ji et al 2006;Schwedler et al 2009).…”

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