Inducible nitric oxide synthase over-expression in arterial myocytes exacerbates neointima formation and atherosclerosis

The therapeutic potential of low molecular-weight fucoidan (LMWF), a sulfated polysaccharide extracted from brown seaweed was investigated on vascular smooth muscle cell (VSMC) and human vascular endothelial cell (HUV-EC-C) proliferation and migration in vitro and in a rat model of intimal hyperplasia. Sprague–Dawley rats were subjected to balloon injury in the thoracic aorta followed by two weeks’ treatment with either LMWF (5 mg/kg/day) or vehicle. Morphological analysis and proliferating cell nuclear antigen immunostaining at day 14 indicated that LMWF prevented intimal hyperplasia in rat thoracic aorta as compared with vehicle (neo-intima area, 3 ± 0.50 mm2 versus 5 ± 0.30 mm2, P < 0.01). In situ zymography showed that LMWF significantly decreased the activity of matrix metalloproteinase (MMP)-2 in the neo-intima compared to vehicle. The in vitro study demonstrated that 10 μg/ml LMWF increased HUV-EC-C migration by 45 ± 5% but reduced VSMC migration by 40 ± 3%. LMWF also increased MMP-2 mRNA expression in HUV-EC-Cs and reduced it in VSMCs. MMP-2 level in the conditioned medium from cells incubated with 10 μg/ml LMWF was 5.4-fold higher in HUV-EC-Cs, but 6-fold lower in VSMCs than in untreated control cells. Furthermore, decreasing MMP-2 expression in HUV-EC-Cs or VSMCs by RNA interference resulted in reduced LMWF-induced effects on cell migration.In conclusion, LMWF increased HUV-EC-C migration and decreased VSMC migration in vitro. In vivo, this natural compound reduced the intimal hyperplasia in the rat aortic wall after balloon injury. Therefore, LMWF could be of interest for the prevention of intimal hyperplasia.