CCN5 modulates the antiproliferative effect of heparin and regulates cell motility in vascular smooth muscle cells

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 α-actin.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.Aberrant proliferation of smooth muscle cells (SMC) is the hallmark of several pathological states, including arteriosclerosis, persistent pulmonary hypertension in the newborn, pyloric stenosis, megaureter, and uterine fibroids. Because vascular SMC (VSMC) hyperplasia is responsible for the failure of a substantial fraction (as high as 30%) of many vascular surgical procedures – including percutaneous transluminal coronary angioplasty, coronary artery bypass grafts, arterio-venous shunts, endarterectomies, and heart transplants – considerable work has focused on the mechanisms regulating VSMC hyperproliferation and on the search for agents that can suppress VSMC mitogenesis. We and others have studied the glycosaminoglycan heparin, which inhibits VSMC proliferation and migration both in cell culture and in animal models [1]. We recently described and characterized a new member of the CCN family of growth factors [2], CCN5, that is induced and maintained by heparin treatment of VSMC and is expre