Effects of enoxaparin and dalteparin on proliferation and migration of patient-derived vascular smooth muscle cells

Background: Proliferation and migration are the two main processes of intimal hyperplasia: the primary cause of intermediate and late vascular graft failure. Low-molecular-weight heparins (LMWHs) inhibit these processes on vascular smooth muscle cells (VSMCs) in animal models, but have failed to improve patency of vascular grafts in clinical trials. Despite these findings, they are still used therapeutically to reduce intimal hyperplasia following vascular interventions. This study was designed to investigate the effects of LMWHs compared to unfractioned heparin in patient-derived VSMCs. Material and methods: Arterial patient-derived VSMCs were used to study the effects of enoxaparin and dalteparin on proliferation, migration and mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK-ERK) signal transduction. The VSMCs were treated with the LMWHs in a range of concentrations and evaluated using image based cell enumeration, real time migration monitoring and flow cytometry. Series treated with unfractioned heparin were included as positive controls and untreated series as negative controls. Results: Neither enoxaparin nor dalteparin influenced proliferation and MAPK-ERK phosphorylation. Migration was reduced slightly by both LMWHs. Unfractioned heparin exhibited dose-dependent effects different from those of the LMWHs in all analyses. Conclusions: This study demonstrated a difference in proliferative and migratory effects between the two LMWHs and unfractioned heparin in patient-derived VSMCs. The effects corresponded to the MAPK-ERK activation, suggesting different mechanisms of action. These results can explain why clinical trials using LMWHs to prevent intimal hyperplasia have failed to observe a reduced incidence of restenosis and do not support prolonged therapeutic use to prevent intimal hyperplasia.