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Heparanase and Syndecan-4 Are Involved in Low Molecular Weight Fucoidan-Induced Angiogenesis

Inserm U1148, Laboratory for Vascular Translational Science, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Groupe Biothérapies et Glycoconjugués, 93000 Bobigny, France
Laboratoire de Biochimie, Hôpital Jean Verdier, Assistance Publique-Hôpitaux de Paris, 93140 Bondy, France
ERL CNRS 9215, CRRET Laboratory, Université Paris Est Créteil, 94010 Créteil, France
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Paola Laurienzo
Mar. Drugs 2015, 13(11), 6588-6608;
Received: 29 July 2015 / Revised: 18 September 2015 / Accepted: 19 October 2015 / Published: 28 October 2015
(This article belongs to the Collection Marine Polysaccharides)
PDF [1701 KB, uploaded 28 October 2015]


Induction of angiogenesis is a potential treatment for chronic ischemia. Low molecular weight fucoidan (LMWF), the sulfated polysaccharide from brown seaweeds, has been shown to promote revascularization in a rat limb ischemia, increasing angiogenesis in vivo. We investigated the potential role of two heparan sulfate (HS) metabolism enzymes, exostosin-2 (EXT2) and heparanase (HPSE), and of two HS-membrane proteoglycans, syndecan-1 and -4 (SDC-1 and SDC-4), in LMWF induced angiogenesis. Our results showed that LMWF increases human vascular endothelial cell (HUVEC) migration and angiogenesis in vitro. We report that the expression and activity of the HS-degrading HPSE was increased after LMWF treatment. The phenotypic tests of LMWF-treated and EXT2- or HPSE-siRNA-transfected cells indicated that EXT2 or HPSE expression significantly affect the proangiogenic potential of LMWF. In addition, LMWF increased SDC-1, but decreased SDC-4 expressions. The effect of LMWF depends on SDC-4 expression. Silencing EXT2 or HPSE leads to an increased expression of SDC-4, providing the evidence that EXT2 and HPSE regulate the SDC-4 expression. Altogether, these data indicate that EXT2, HPSE, and SDC-4 are involved in the proangiogenic effects of LMWF, suggesting that the HS metabolism changes linked to LMWF-induced angiogenesis offer the opportunity for new therapeutic strategies of ischemic diseases. View Full-Text
Keywords: fucoidan; angiogenesis; human endothelial cell; glycosaminoglycan; syndecan; heparanase fucoidan; angiogenesis; human endothelial cell; glycosaminoglycan; syndecan; heparanase

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Haddad, O.; Guyot, E.; Marinval, N.; Chevalier, F.; Maillard, L.; Gadi, L.; Laguillier-Morizot, C.; Oudar, O.; Sutton, A.; Charnaux, N.; Hlawaty, H. Heparanase and Syndecan-4 Are Involved in Low Molecular Weight Fucoidan-Induced Angiogenesis. Mar. Drugs 2015, 13, 6588-6608.

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