title: CCN5 modulates the antiproliferative effect of heparin and regulates cell motility in vascular smooth muscle cells.
abstract: BACKGROUND: Vascular smooth muscle cell (VSMC) hyperplasia plays an important role in both chronic and acute vascular pathologies including atherosclerosis and restenosis. Considerable work has focused on the mechanisms regulating VSMC proliferation and motility. Earlier work in our lab revealed a novel growth arrest-specific (gas) gene induced in VSMC exposed to the antiproliferative agent heparin. This gene is a member of the CCN family and has been given the name CCN5. The objective of the present study is to elucidate the function of CCN5 protein and to explore its mechanism of action in VSMC. RESULTS: Using RNA interference (RNAi), we first demonstrate that CCN5 is required for the antiproliferative effect of heparin in VSMC. We also use this gene knockdown approach to show that CCN5 is an important negative regulator of motility. To explore the mechanism of action of CCN5 on VSMC motility, we use RNAi to demonstrate that knock down of CCN5 up regulates expression of matrix metalloproteinase-2 (MMP-2), an important stimulator of motility in VSMC. In addition, forced expression of CCN5 via adenovirus results in reduced MMP-2 activity, this also corroborates the gene knock down results. Finally, we show that loss of CCN5 expression in VSMC causes changes in VSMC morphology and cytoskeletal organization, including a reduction in the amount and macromolecular assembly of smooth muscle cell alpha-actin. CONCLUSIONS: This work provides important new insights into the regulation of smooth muscle cell proliferation and motility by CCN5 and may aid the development of therapies for vascular diseases.
authors.affiliation: Department of Anatomy and Cell Biology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA. john.castellot@tufts.edu
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Lake
authors.forename: John J
authors.initials: JJ
authors.lastname: Castellot