Antiproliferative capacity of synthetic dextrans on smooth muscle cell growth: the model of derivatized dextrans as heparin-like polymers

Abstract

Proliferation of vascular smooth muscle cells (SMC) is postulated to be a key step in the pathogenesis of atherosclerosis or restenosis after vascular interventions such as angioplasty. Natural glycosaminoglycans, such as heparin and heparan sulfate, are known for their ability to inhibit SMC proliferation in vivo and in vitro. The antiproliferative activity of synthetic derivatized dextrans exhibiting heparin-like anticoagulant and anticomplement capacities have been investigated with rat aorta smooth muscle cells in culture. We report here that some derivatized dextrans grafted with benzylamide sulfonate moieties are potent antiproliferative agents for rat smooth muscle cell (SMC) in vitro. These synthetic polymers inhibit the SMC proliferation as well as heparin. The SMC growth inhibition is dose dependent, reversible and non-toxic. Highly anionic carboxylic dextrans are not capable of inhibiting the SMC growth, excluding a simple charge effect mechanism. Using fluorescent (DTAF) probes, we demonstrated that the synthetic antiproliferative polymers and heparin are internalized into the SMC. No binding or internalization was observed with native dextran devoid of antiproliferative capacity. We conclude that a suitable distribution of functional groups on the dextran backbone can simulate heparin activity in terms of antiproliferative capacity on SMC growth.