Structural Determinant and Its Underlying Molecular Mechanism of STPC2 Related to Anti-Angiogenic Activity

Abstract

In this study, we aimed to use different strategies to further uncover the anti-angiogenic molecular mechanism of a fucoidan-like polysaccharide STPC2, isolated from brown alga Sargassum thunbergii. A desulfated derivative, STPC2-DeS, was successfully prepared and identified. The native polysaccharide and desulfated product were subjected to evaluate their anti-angiogenic effects. In the tube formation assay, STPC2 showed dose-dependent inhibition. In addition, STPC2 could distinctly inhibit the permeation of HUVEC cells into the lower chamber. Moreover, a significant reduction of microvessel density was observed in chick chorioallantoic membrane assay treated with STPC2. Meanwhile, STPC2 was found to repress the VEGF-induced neovessel formation in the matrigel plug assay in vivo. However, STPC2-DeS failed to suppress the anti-angiogenic activity via these in vitro and in vivo strategies. In addition, we demonstrated that STPC2 could significantly downregulate the phosphorylation of VEGFR2 and its related downstream Src family kinase, focal adhesion kinase, and AKT kinase. Furthermore, surface plasmon resonance assay revealed that STPC2 bound strongly to VEGF to interfere with VEGF–VEGFR2 interaction. Taken together, these results evidently demonstrated that STPC2 exhibited a potent anti-angiogenic activity through binding to VEGF via sulfated groups to impede VEGF–VEGFR2 interaction, thus affected the downstream signaling molecules.

Antibacterial and Antioxidant Capacities and Attenuation of Lipid Accumulation in 3T3-L1 Adipocytes by Low-Molecular-Weight Fucoidans Prepared from Compressional-Puffing-Pretreated Sargassum Crassifolium

“…The fucose contents for SCO, SCA, SCOA, and SCH were 24.53% ± 1.89%, 31.64% ± 1.91%, 33.20% ± 0.54%, and 30.53% ± 1.89%, respectively, which were in general higher than that of SC (25.87% ± 1.09%), suggesting that the degradation reagents may increase the fucose content of LMW fucoidans ( Table 1 ). The sulfate content of fucoidan plays a critical role in the biological functions as previously noted by other investigators [ 25 , 26 ]. Therefore, we measured the sulfate contents for SCO, SCA, SCOA, and SCH and the percentages were 17.47% ± 1.35%, 22.37% ± 0.98%, 22.23% ± 1.09%, and 19.77% ± 1.01%, respectively, which were significantly higher than that of SC (15.12% ± 0.67%), suggesting that degradation reagents may also increase the sulfate content of fucoidan ( Table 1 ).…”

Effects of Fucoidans from Five Different Brown Algae on Oxidative Stress and VEGF Interference in Ocular Cells

“…VEGF antibody-derived compounds bevacizumab and ranibizumab, as well as the fusion protein aflibecept, interact with specific amino acids in the receptor-binding domain of VEGF, causing a steric inhibition of the binding of VEGF to its receptor [36], with differences in affinities between the compounds [37]. The interaction of fucoidan and other heparin-related compounds is complex, however, depending on features such as sulfation and molecular weight [38,39]. Furthermore, fucoidan has been shown to also have a binding affinity to VEGF receptors and to facilitate the internalization of VEGF receptors, blocking the binding and in-vitro functions of VEGF [38,40,41].…”

Molecular Targets and Related Biologic Activities of Fucoidan: A Review

“…Vascular endothelial growth factors (VEGF) have been considered as the targets to inhibit deregulated blood vessel formation, which influences endothelial cell proliferation, migration, invasion and vascularization [ 51 , 52 ]. Interaction between VEGF receptor 2 (VEGFR2) and VEGF can be disrupted by fucoidan through binding to both VEGF and VEGFR2, inactivating VEGFR2/Erk/VEGF-signaling pathway in HMEC-1 cells [ 51 ].…”

“…Interaction between VEGF receptor 2 (VEGFR2) and VEGF can be disrupted by fucoidan through binding to both VEGF and VEGFR2, inactivating VEGFR2/Erk/VEGF-signaling pathway in HMEC-1 cells [ 51 ]. VEGF recognizes sulfated groups of fucoidan to impede VEGF/VEGFR2 interaction, thus affecting the downstream signaling molecules including Src family kinase, focal adhesion kinase and AKT kinase ( Table 1 ) [ 52 ].…”