Low-Molecular-Weight Fucoidan Promotes Therapeutic Revascularization in a Rat Model of Critical Hindlimb Ischemia

Abstract

The therapeutic potential of low-molecular-weight (LMW) fucoidan, a sulfated polysaccharide extracted from brown seaweed devoid of direct antithrombin effect, was investigated in vitro and in a model of critical hindlimb ischemia in rat. In vitro results showed that LMW fucoidan enhanced fibroblast growth factor (FGF)-2-induced [ 3 H]thymidine incorporation in cultured rat smooth muscle cells. Intravenous injection in rats of LMW fucoidan significantly increased the stromal-derived factor (SDF)-1 level from 1.2 Ϯ 0.1 to 6.5 Ϯ 0.35 ng/ml in plasma. The therapeutic effect of LMW fucoidan (5 mg/kg/day), FGF-2 (1 g/kg/day), and LMW fucoidan combined with FGF-2 was assessed 14 days after induction of ischemia by 1) clinical evaluation of claudication, 2) tissue blood flow analysis, 3) histoenzymology of muscle metabolic activity, and 4) quantification of capillary density. Both LMW fucoidan and FGF-2 similarly improved residual muscle blood flow (62.5 Ϯ 6.5 and 64.5 Ϯ 4.5%, respectively) compared with the control group (42 Ϯ 3.5%, p Ͻ 0.0001). The combination of FGF-2 and LMW fucoidan showed further significant improvement in tissue blood flow (90.5 Ϯ 3%, p Ͻ 0.0001). These results were confirmed by phosphorylase activity, showing muscle regeneration in rats treated with the combination of FGF-2 and LMW fucoidan. Capillary density count increased from 9.6 Ϯ 0.7 capillaries/muscle section in untreated ischemic controls to 14.3 Ϯ 0.9 with LMW fucoidan, 14.5 Ϯ 0.9 with FGF-2, and 19

Expression of Stromal Cell-Derived Factor-1 and of Its Receptor CXCR4 in Liver Regeneration from Oval Cells in Rat

“…39 An effect mediated by fibroblast growth factor is nonetheless unlikely since fucoidan has been shown to potentiate in vivo its proliferative effects. 40 By contrast, we cannot exclude that fucoidan may have exerted its effects by increasing the antiproliferative activity of transforming growth factor-␤. 39 Use of specific pharmacological inhibitors of CXCR4 or of SDF-1, when available, will be mandatory to clarify the exact role played by the SDF-1/CXCR4 couple during liver regeneration from oval cells.…”

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

“…The promising efficacy of G-CSF in supporting organ regeneration in animal studies is currently being tested in clinical trials [78]. Alternatively, promoting SDF-1 signaling could also be achieved by fucoidan-mediated SDF-1 elevation [79], or direct activation of the CXCR4 pathway with SDF-1 agonists [49], with FTY720, a sphingosine-1-phosphate analog that activates CXCR4 signaling [80] or soluble molecules priming CXCR4 + cells such as complement C3a [81].…”

Efficacy and safety of a new-class hemostatic drug candidate, AV513, in dogs with hemophilia A

“…[10][11][12][13] Low molecular weight fucoidan (8 kDa) has been shown to regulate neo-intimal formation and endothelial cell proliferation. [14][15][16] The observed effect on vascular cells is suggested to be due to the enhanced half-life of fibroblast growth factor through fucoidan binding. Unfractionated fucoidans, from various sources, are heterogeneous sulfated polysaccharides and may differ substantially in size and exhibit structural diversity.…”