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.
Highlights
Heparan sulfate proteoglycans (HSPG) are integral components of the cell surface and extracellular matrix (ECM) of animal cells
2D-angiogenesis assay, we demonstrated that Low molecular weight fucoidan (LMWF) induced the formation of capillary tubes in Matrigel by increasing their length by 4 fold and their area up to 84% ± 8%, as compared to untreated (UT) control cells (Figure 1C)
We have previously shown the therapeutic potential of low molecular weight fucoidan (LMWF) in reduction of in-stent restenosis in a rabbit model, vascular tissue repair [21], and in critical hind limb ischemia in a rat model [7]
Summary
Heparan sulfate proteoglycans (HSPG) are integral components of the cell surface and extracellular matrix (ECM) of animal cells These complex molecules consist of sulfated carbohydrate chains of glycosaminoglycans (GAGs) covalently bound to a protein core. Low molecular weight fucoidan (LMWF), a sulfated polysaccharide from brown seaweeds that mimics some biological activities of heparin, has been shown to promote revascularization in a rat critical hindlimb ischemia [7]. It increases human vascular endothelial growth factor (VEGF165)-induced endothelial cell migration by enhancing VEGF165 binding to VEGFR-2 and neuropilin 1 (NRP1) [8]. We hypothesized that LMWF (8 kDa) from Fucus vesiculosus can modify the amount and the distribution of heparan sulfate (HS) chains exposed at the endothelial cell surface and of two major heparan sulfate membrane proteoglycans, SDC-1 and SDC-4, causing modifications of cell properties related to proangiogenic abilities
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