Inflammatory cytokines stimulate vascular smooth muscle cells locomotion and growth by enhancing alpha5beta1 integrin expression and function.
The formation of atherosclerotic lesions requires the migration of vascular smooth muscle cells from the media into the intima of the artery and their proliferation. These events, which are preceded and accompanied by inflammation, are modulated by integrin receptors linking vascular smooth muscle cells to extracellular matrix molecules. Among them, fibronectin induces vascular smooth muscle cells to acquire the phenotype they show in the atherosclerotic plaque. Here we show that amounts of interleukin-1 beta, tumor necrosis factor alpha and interferon-gamma as possibly released by activated immune cells infiltrating atherosclerotic lesions, upregulate vascular smooth muscle cell expression of the alpha5beta1 integrin, a fibronectin receptor. This improves vascular smooth muscle cell capability of migrating toward soluble or anchored fibronectin and of adhering to immobilized fibronectin. The latter effect, in turn, augments vascular smooth muscle cell proliferative response to mitogens, as suggested by the increase of intracellular pH. Finally, the effects that inflammatory cytokines have on vascular smooth muscle cell locomotion and growth, are specifically blocked by anti-alpha5beta1 antibodies. As fibronectin and alpha5beta1 levels are augmented in vivo in the atherosclerotic plaques, these findings support the use of integrin antagonists as potential adjuvants in atherosclerosis treatment.
Barillari
G
G
Department of Experimental Medicine, University 'Tor Vergata', 00133, Rome, Italy.
Albonici
L
L
Incerpi
S
S
Bogetto
L
L
Pistritto
G
G
Volpi
A
A
Ensoli
B
B
Manzari
V
V
D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D017931:DNA Primers / Q000737:chemistry; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D008969:Molecular Sequence Data; D024510:Muscle Development; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000378:metabolism; D017469:Receptors, Fibronectin / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D016207:Cytokines; D017931:DNA Primers; D007375:Interleukin-1; D017469:Receptors, Fibronectin; D014409:Tumor Necrosis Factor-alpha; D016222:Fibroblast Growth Factor 2; D012313:RNA; D007371:Interferon-gamma