Modified C‐Reactive Protein Is Expressed by Stroke Neovessels and Is a Potent Activator of Angiogenesis In Vitro

Abstract

Native C-reactive protein (nCRP) is a pentameric oligo-protein and an acute phase reactant whose serum expression is increased in patients with inflammatory disease. We have identified by immunohistochemistry, significant expression of a tissue-binding insoluble modified version or monomeric form of CRP (mCRP) associated with angiogenic microvessels in peri-infarcted regions of patients studied with acute ischaemic stroke. mCRP, but not nCRP was expressed in the cytoplasm and nucleus of damaged neurons. mCRP co-localized with CD105, a marker of angiogenesis in regions of revascularisation. In vitro investigations demonstrated that mCRP was preferentially expressed in human brain microvessel endothelial cells following oxygen-glucose deprivation and mCRP (but not column purified nCRP) associated with the endothelial cell surface, and was angiogenic to vascular endothelial cells, stimulating migration and tube formation in matrigel more strongly than fibroblast growth factor-2. The mechanism of signal transduction was not through the CD16 receptor. Western blotting showed that mCRP stimulated phosphorylation of the key down-stream mitogenic signalling protein ERK1/2. Pharmacological inhibition of ERK1/2 phosphorylation blocked the angiogenic effects of mCRP. We propose that mCRP may contribute to the neovascularization process and because of its abundant presence, be important in modulating angiogenesis in both acute stroke and later during neuro-recovery.

Regulated conformation changes in C-reactive protein orchestrate its role in atherogenesis

“…This has led us to propose that the dissociation of the CRP molecule is an activating mechanism that is required for the expression of enhanced bioactivities and is also a buffering mechanism that localizes the actions of mCRP into inflammatory loci to prevent the possible global effects directly induced by large-scale alterations in the serum levels of CRP [73]. Consistent with our proposal, immunohistochemical analyses using highly specific antibodies revealed that mCRP, not CRP, was the major isoform present in local lesions, including atherosclerotic plaques [55,76], diabetic kidneys [77] and stroke neovessels [78].…”

Biological actions of pentraxins

“…Studies from our group and others have also demonstrated that CRP and PTX3 distribution within the atherosclerotic lesions distinctly differs [11,32]. For instance: 1) PTX3 and not CRP is augmented in complicated plaques compared to fibroatheroma whereas CRP but not PTX3 is more accumulated in fibroatheroma than in atheroma; 2) PTX3 is found to be quite sparse in lipid-rich regions of the fibroatheroma lesions whereas CRP is found to be particularly intense surrounding and within the lipid core; 3) PTX3 and CRP colocalize with macrophages but PTX3 and not CRP correlates with the extent of M2 macrophage phenotype (presents anti-inflammatory properties); and, 4) although PTX3 is notably abundant in areas of intraplaque hemorrhage where CRP is scarce, CRP has been strongly detected around areas of newly formed microvessels suggesting CRP contribution to neovascularization [11,33,34]. Overall, these observations suggest that CRP and PTX3 may play distinct biological roles in atherosclerosis and ensuing thrombotic complications.…”

Dissociation of Pentameric to Monomeric C-Reactive Protein Localizes and Aggravates Inflammation

“…However, it must be taken into consideration that the therapeutic inhibition of mCRP generation might reduce the proangiogenic effect of mCRP that has been described recently. 34 Inflammation as such is not necessarily harmful, but uncontrolled inflammation may be detrimental in conditions such as ischemia/ reperfusion injury. Similarly, the proangiogenic effects of mCRP may be beneficial; however, in the context of an exaggerated inflammatory response, they may have less relevance.…”