Low-molecular-weight fucoidan promotes therapeutic revascularization in a rat model of critical hindlimb ischemia.
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 +/- 0.1 to 6.5 +/- 0.35 ng/ml in plasma. The therapeutic effect of LMW fucoidan (5 mg/kg/day), FGF-2 (1 micro 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 +/- 6.5 and 64.5 +/- 4.5%, respectively) compared with the control group (42 +/- 3.5%, p < 0.0001). The combination of FGF-2 and LMW fucoidan showed further significant improvement in tissue blood flow (90.5 +/- 3%, p < 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 +/- 0.7 capillaries/muscle section in untreated ischemic controls to 14.3 +/- 0.9 with LMW fucoidan, 14.5 +/- 0.9 with FGF-2, and 19.1 +/- 0.9 in combination (p < 0.001). Thus, LMW fucoidan potentiates FGF-2 activity, mobilizes SDF-1, and facilitates angiogenesis in a rat model. This natural compound could be of interest as an alternative for conventional treatment in critical ischemia.
Luyt
Charles-Edouard
CE
Institut National de la Santé et de la Recherche Médicale U460, CHU X. Bichat, Paris, France.
Meddahi-Pellé
Anne
A
Ho-Tin-Noe
Benoit
B
Colliec-Jouault
Sylvia
S
Guezennec
Jean
J
Louedec
Liliane
L
Prats
Hervé
H
Jacob
Marie-Paule
MP
Osborne-Pellegrin
Mary
M
Letourneur
Didier
D
Michel
Jean-Baptiste
JB
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D002196:Capillaries / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000097:blood; D004195:Disease Models, Animal; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008970:Molecular Weight; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D010477:Perfusion; D006005:Phosphorylases / Q000378:metabolism; D011134:Polysaccharides / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013936:Thymidine / Q000378:metabolism
D000925:Anticoagulants; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D011134:Polysaccharides; C007789:fucoidan; D006005:Phosphorylases; D020780:Matrix Metalloproteinase 9; D013936:Thymidine