Although remodeling of vessels can dramatically alter lumen diameter and clinical sequelae, the molecular mechanisms regulating extracellular matrix turnover and remodeling are still not well understood. In vitro studies have suggested that adhesive events strongly regulate fibroblast contraction and expression of matrix metalloproteinases (MMPs). To investigate remodeling and contraction in human smooth muscle (SMC), we have compared their culture on monomer and polymerized collagen gels, conditions that mimic some of the features of injured and normal vessels, respectively. We demonstrate that polymerized collagen activates the transcriptional factor NF-kappaB in human aortic SMC and that NF-kappaB induction of MMP1 and α2 integrin is required for collagen degradation and contraction. Overexpression of either of these two NF-kappaB gene products can rescue blockade of collagen gel contraction by overexpression of the NF-kappaB inhibitor IkappaBα. MMP2 activation is also induced by polymerized collagen, but is independent of NF-kappaB transcriptional activation. The pericellular activation of MMP-2 is particularly enhanced by the Discoidin Receptor-2 (DDR-2), a recently identified tyrosine kinase receptor for collagen expressed on SMC in culture and in lesions of atherosclerosis. Polymerized collagen-induced activation of MMP-2 is independent of DDR2 tyrosine phosphorylation, but requires portions of the DDR2 cytoplasmic domain. Our data provide evidence for a central role for NF-kappaB gene products and DDR2 in the tightly regulated process of SMC remodeling of the extracellular matrix.
Regulation of extracellular matrix remodeling by smooth muscle cells / E.Raines, N. Ferri. - In: ATHEROSCLEROSIS SUPPLEMENTS. - ISSN 1567-5688. - 4:2(2003), pp. 13-13. ((Intervento presentato al 13. convegno 13th International Symposium on Atherosclerosis tenutosi a KYOTO, JAPAN nel 2003.
|Titolo:||Regulation of extracellular matrix remodeling by smooth muscle cells|
FERRI, NICOLA (Ultimo)
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||2003|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/S1567-5688(03)90052-3|
|Appare nelle tipologie:||01 - Articolo su periodico|