An NF-κB-dependent transcriptional program is required for collagen remodeling by human smooth muscle cells

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. To investigate these processes in human smooth muscle, 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 show that culture on polymerized, but not monomer, collagen leads to the activation of the transcription factor NF-κB through phosphorylation and degradation of its inhibitor, IκBα. Coincident with NF-κB activation, expression of MMP1, MMP2, and α₂ integrin increases on polymerized collagen. Specific inhibition of NF-κB by retroviral overexpression of wild-type IκBα or phosphorylation-resistant, IκBα-stabilized mutant (IκBαSer^32,36/Ala) reverses the increases in MMP1 and α₂β₁ on polymerized collagen and decreases collagen gel contraction and degradation. However, forced overexpression of α₂β₁ integrin or MMP1 in smooth muscle cells expressing IκBα^Ser32,36/Ala rescues their ability to contract collagen gels. Thus, polymerized collagen induces NF-κB-dependent expression of MMP1 and α₂β₁ integrin, that are required for smooth muscle extracellular matrix remodeling.