Modified C-reactive protein is expressed by stroke neovessels and is a potent activator of angiogenesis in vitro.
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.
Slevin
Mark
M
School of Biology, Chemistry and Health Science, Manchester Metropolitan University, Manchester, UK. m.a.slevin@mmu.ac.uk
Matou-Nasri
Sabine
S
Turu
Marta
M
Luque
Ana
A
Rovira
Norma
N
Badimon
Lina
L
Boluda
Susana
S
Potempa
Lawrence
L
Sanfeliu
Coral
C
de Vera
Nuria
N
Krupinski
Jerzy
J
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000906:Antibodies / Q000737:chemistry; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002196:Capillaries / Q000473:pathology; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005260:Female; D005333:Fetus / Q000166:cytology / Q000502:physiology; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000172:deficiency; D006801:Humans; D000860:Hypoxia / Q000473:pathology; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017452:Receptors, IgG / Q000378:metabolism; D020521:Stroke / Q000235:genetics* / Q000473:pathology
D000906:Antibodies; D047428:Protein Kinase Inhibitors; D017452:Receptors, IgG; D002097:C-Reactive Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose