The actin cytoskeleton regulates matrix‐metalloproteinase‐2 expression in vascular smooth muscle cells in response to insulin‐like growth factor

Abstract

Vascular smooth muscle cells (VSMCs) can display a variety of phenotypes from a differentiated contractile phenotype to a de‐differentiated migratory one. This plasticity facilitates VSMC participation in vessel remodeling events like atherogenesis. The cytoskeleton can regulate the expression of contractile genes through the actin‐mediated regulation of myocardin‐related transcription factor (MRTF)‐A. We asked if the cytoskeleton was capable of regulating factors associated with the de‐differentiated phenotype, namely, matrix‐metalloproteinase (MMP)‐2. We used insulin‐like growth factor‐1 (IGF‐1) to induce VSMC de‐differentiation, which was characterized by changes in the actin cytoskeleton and a decreased level of the contractile marker smooth muscle α‐actin, and found that IGF‐1 induced up‐regulation of MMP‐2. Alteration of the actin cytoskeleton affected this regulation. Co‐stimulation of VSMCs with IGF‐1 and the F‐actin stabilizing agent jasplakinolide blocked MMP‐2 up‐regulation, while the F‐actin de‐stabilizing agent latrunculin B enhanced up‐regulation. These data suggest that the F‐actin cytoskeleton plays an inhibitory role in the regulation of MMP‐2 in VSMCs. Since MRTF‐A is critical for regulation of the contractile genes in VSMCs, future work will determine the role of MRTF‐A in MMP‐2 regulation. (Funding: NIH R01 GM60651)Grant Funding SourceNIH