Heparin inhibition of human vascular smooth muscle cell hyperplasia

Background: Vascular smooth muscle cell (VSMC) growth is responsible for intimal hyperplasia, a major cause of failure after vascular surgery and angioplasty. Heparin is the first described inhibitor of VSMC growth, but has not proved effective in the prevention of human intimal hyperplasia. Heparin is a heterogenous substance, which may contain a mixture of components which differ in antiproliferative activity. Isolation of an active component may favourably influence its therapeutic profile. Methods and results: Growth of human VSMC cultured from operative specimens, assessed by cell counting and labelled thymidine incorporation was used as a model of VSMC proliferation in intimal hyperplasia. Unfractionated (UFH) and low molecular weight (LMWH) heparins inhibit cell growth and thymidine uptake by human VSMCs in response to 15% foetal calf serum. UFHs are more active than LMWHs and this difference increases with increasing heparin dose. To confirm this effect, size-based fractions of heparin were prepared by gel permeation chromatography, and characterised by high performance liquid chromatography. High molecular weight fractions (MW > 21000) have higher activity than fractions of medium (MW 12000-21000) or low molecular weight (MW < 12000). These differences become more pronounced at higher dose, and are statistically significant at 100 μg/ml (Mann-Whitney, p < 0.05). Conclusions: The antiproliferative activity of heparin appears to be maximal in its high molecular weight component.