Low-Molecular-Weight Fucoidan Induces Endothelial Cell Migration via the PI3K/AKT Pathway and Modulates the Transcription of Genes Involved in Angiogenesis

Abstract

Low-molecular-weight fucoidan (LMWF) is a sulfated polysaccharide extracted from brown seaweed that presents antithrombotic and pro-angiogenic properties. However, its mechanism of action is not well-characterized. Here, we studied the effects of LMWF on cell signaling and whole genome expression in human umbilical vein endothelial cells and endothelial colony forming cells. We observed that LMWF and vascular endothelial growth factor had synergistic effects on cell signaling, and more interestingly that LMWF by itself, in the absence of other growth factors, was able to trigger the activation of the PI3K/AKT pathway, which plays a crucial role in angiogenesis and vasculogenesis. We also observed that the effects of LMWF on cell migration were PI3K/AKT-dependent and that LMWF modulated the expression of genes involved at different levels of the neovessel formation process, such as cell migration and cytoskeleton organization, cell mobilization and homing. This provides a better understanding of LMWF’s mechanism of action and confirms that it could be an interesting therapeutic approach for vascular repair.

Fucoidan‐induced osteogenic differentiation promotes angiogenesis by inducing vascular endothelial growth factor secretion and accelerates bone repair

“…Luyt et al (2003) found that fucoidan alone or in combination with basic FGF significantly improved revascularization. Furthermore, Bouvard et al (2015) showed that low molecular weight fucoidan induced HUVEC migration. Together, these findings suggest that the discrepancies between the results of previous studies are related to the molecular weight and sulfate content as well as the different seaweed species and extraction methods used (Koyanagi, Tanigawa, Nakagawa, Soeda, & Shimeno, 2003;Matsubara et al, 2005).…”

“…A recent study has also shown that fucoidan exerts an angiogenic effect through its action on protein kinase B (AKT)/matrix metalloproteinase-2 (MMP-2) signalling (Kim, Park, Kang, Kim, & Lee, 2014). Additionally, Bouvard et al (2015) reported that fucoidan induces endothelial cell migration and modulates the transcription of genes involved in angiogenesis, and Lake et al (2006) reported that fucoidan enhances vascular endothelial growth factor (VEGF)-induced endothelial cell migration.…”

Use of Marine Compounds to Treat Ischemic Diseases

“…Pseudotube formation induced by fucoidan correlates in vitro with overexpression of the 6 integrin subunit on the endothelial cell surface [83,102]. This 6 overexpression results from transcriptional upregulation.…”

“…Fucoidan binds to the cell membrane and can thereby induce cellular responses analogous to signal transduction by growth factors. It is thus able to modulate the expression of genes involved at different stages of neovessel formation, such as cell migration, cytoskeleton organization, cell mobilization, and homing [102].…”

“…In his excellent review of sulphated fucans and galactans, Pomin forwards a mechanism to explain the antiinflammatory properties of marine polysaccharides that could also account for the impact of fucoidan on EPC recruitment [105]. The molecular mechanisms behind these proangiogenic properties would involve ( Figure 8): i) impaired binding of stem cells to the endothelium via fucoidan binding to P-and/or L-selectins which play a central role in the inflammatory response triggered by ischemia (P-selectin is upregulated on endothelial cells and platelets during ischemic disorders) [102,106] and, most likely, ii) disruption of the SDF-1 gradient between blood and bone marrow or ischemic tissue. This would modify the chemokine gradient that sustains the homing of stem cells/leukocytes to ischemic sites and promotes their mobilization.…”