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

Haddad O, Guyot E, Marinval N, Chevalier F, Maillard L, Gadi L, Laguillier-Morizot C, Oudar O, Sutton A, Charnaux N, Hlawaty H - Mar Drugs (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Inserm U1148, Laboratory for Vascular Translational Science, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Groupe Biothérapies et Glycoconjugués, 93000 Bobigny, France. haddad.oualid@univ-paris13.fr.

ABSTRACT
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.

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Effects of LMWF on the SDC distribution in rat balloon injured artery. SDC-1 and SDC-4 expressions were assessed using immunohistochemistry in rat model of intimal hyperplasia. (A) SDC-1 or (D) SDC-4 expressions in non injured arteries; (B) SDC-1 or (E) SDC-4 expressions in injured arteries treated with NaCl; (C) SDC-1 or (F) SDC-4 expressions in injured arteries treated with LMWF. White arrows indicate SDC expressions in the neointima layer in high power view inserts (red). Green: autofluorescence of the elastic fibers of the lamina. Magnification ×100, L: lumen, N: neointima, M: media, A: adventitia.
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marinedrugs-13-06588-f005: Effects of LMWF on the SDC distribution in rat balloon injured artery. SDC-1 and SDC-4 expressions were assessed using immunohistochemistry in rat model of intimal hyperplasia. (A) SDC-1 or (D) SDC-4 expressions in non injured arteries; (B) SDC-1 or (E) SDC-4 expressions in injured arteries treated with NaCl; (C) SDC-1 or (F) SDC-4 expressions in injured arteries treated with LMWF. White arrows indicate SDC expressions in the neointima layer in high power view inserts (red). Green: autofluorescence of the elastic fibers of the lamina. Magnification ×100, L: lumen, N: neointima, M: media, A: adventitia.

Mentions: Our results demonstrated that the expression of SDC-1 and SDC-4 was very low in healthy arteries in the media (M) and adventitia (A) layers, whereas it increased in the neointima (N), media and adventitia layers in balloon-injured, and NaCl-treated arteries (vehicle), leading to development of intimal hyperplasia (Figure 5A–E). The LMWF treatment of injured artery increased SDC-1 expression in the neointima and in the adventitia layers, as compared to vehicle (Figure 5C). Furthermore, upon LMWF treatment, the SDC-4 expression was decreased in the neointima and media, but largely increased in the adventitia layer, as compared to vehicle (Figure 5F). These in vivo results were in concordance with our previously described observation obtained in the HUVECs in vitro culture [10].


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

Haddad O, Guyot E, Marinval N, Chevalier F, Maillard L, Gadi L, Laguillier-Morizot C, Oudar O, Sutton A, Charnaux N, Hlawaty H - Mar Drugs (2015)

Effects of LMWF on the SDC distribution in rat balloon injured artery. SDC-1 and SDC-4 expressions were assessed using immunohistochemistry in rat model of intimal hyperplasia. (A) SDC-1 or (D) SDC-4 expressions in non injured arteries; (B) SDC-1 or (E) SDC-4 expressions in injured arteries treated with NaCl; (C) SDC-1 or (F) SDC-4 expressions in injured arteries treated with LMWF. White arrows indicate SDC expressions in the neointima layer in high power view inserts (red). Green: autofluorescence of the elastic fibers of the lamina. Magnification ×100, L: lumen, N: neointima, M: media, A: adventitia.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663543&req=5

marinedrugs-13-06588-f005: Effects of LMWF on the SDC distribution in rat balloon injured artery. SDC-1 and SDC-4 expressions were assessed using immunohistochemistry in rat model of intimal hyperplasia. (A) SDC-1 or (D) SDC-4 expressions in non injured arteries; (B) SDC-1 or (E) SDC-4 expressions in injured arteries treated with NaCl; (C) SDC-1 or (F) SDC-4 expressions in injured arteries treated with LMWF. White arrows indicate SDC expressions in the neointima layer in high power view inserts (red). Green: autofluorescence of the elastic fibers of the lamina. Magnification ×100, L: lumen, N: neointima, M: media, A: adventitia.
Mentions: Our results demonstrated that the expression of SDC-1 and SDC-4 was very low in healthy arteries in the media (M) and adventitia (A) layers, whereas it increased in the neointima (N), media and adventitia layers in balloon-injured, and NaCl-treated arteries (vehicle), leading to development of intimal hyperplasia (Figure 5A–E). The LMWF treatment of injured artery increased SDC-1 expression in the neointima and in the adventitia layers, as compared to vehicle (Figure 5C). Furthermore, upon LMWF treatment, the SDC-4 expression was decreased in the neointima and media, but largely increased in the adventitia layer, as compared to vehicle (Figure 5F). These in vivo results were in concordance with our previously described observation obtained in the HUVECs in vitro culture [10].

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Inserm U1148, Laboratory for Vascular Translational Science, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Groupe Biothérapies et Glycoconjugués, 93000 Bobigny, France. haddad.oualid@univ-paris13.fr.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus