Low molecular weight fucoidan prevents neointimal hyperplasia in rabbit iliac artery in-stent restenosis model

Abstract

Objective - Smooth muscle cell (SMC) proliferation within the intima is regulated by heparan sulfates. We studied a low molecular weight (LMW) fucoidan (sulfated polysaccharide from brown seaweed) on SMC proliferation in vitro and intimal hyperplasia in vivo. Methods and Results - In vitro study revealed that LMW fucoidan reduces rabbit SMC proliferation and is internalized in SMC perinuclear vesicles. On rabbit iliac arteries perfused in vivo with fluorolabeled LMW fucoidan after angioplasty, the labeling was mainly located on sites of injury. Pharmacokinetic studies showed that LMW fucoidan exhibited in rats an elimination half-life of 56±25 minutes (n=8) after intravenous administration and a constant plasma rate for ≥6 hours after intramuscular administration. After stent implantation in their iliac arteries, rabbits were also treated with LMW fucoidan (5 mg/kg IM twice a day). Histomorphometric analysis at day 14 indicated that LMW fucoidan reduced intimal hyperplasia by 59% (1.79±0.4 versus 0.73±0.2 mm2, P<0.0001) and luminal cross-sectional area narrowing by 58% (0.38±0.08 versus 0.16±0.04, P<0.0001). Blood samples showed no anticoagulant activity due to LMW fucoidan. Conclusions - This natural polysaccharide with high affinity for SMCs and sustained plasma concentration markedly reduced intimal hyperplasia, suggesting its use for the prevention of human in-stent restenosis.