Abstract
Critical limb ischemia (CLI) induces the secretion of paracrine signals, leading to monocyte recruitment and thereby contributing to the initiation of angiogenesis and tissue healing. We have previously demonstrated that fucoidan, an antithrombotic polysaccharide, promotes the formation of new blood vessels in a mouse model of hindlimb ischemia. We examined the effect of fucoidan on the capacity of peripheral blood monocytes to adhere and migrate. Monocytes negatively isolated with magnetic beads from peripheral blood of healthy donors were treated with fucoidan. Fucoidan induced a 1.5-fold increase in monocyte adhesion to gelatin (p < 0.05) and a five-fold increase in chemotaxis in Boyden chambers (p < 0.05). Fucoidan also enhanced migration 2.5-fold in a transmigration assay (p < 0.05). MMP9 activity in monocyte supernatants was significantly enhanced by fucoidan (p < 0.05). Finally, Western blot analysis of fucoidan-treated monocytes showed upregulation of ERK/p38 phosphorylation. Inhibition of ERK/p38 phosphorylation abrogated fucoidan enhancement of migration (p < 0.01). Fucoidan displays striking biological effects, notably promoting monocyte adhesion and migration. These effects involve the ERK and p38 pathways, and increased MMP9 activity. Fucoidan could improve critical limb ischemia by promoting monocyte recruitment.
Highlights
Cardiovascular disease is the leading cause of death worldwide
We found that fucoidan did not modulate integrin or receptor expression on the monocyte cell membrane
Fucoidan enhanced monocyte migration towards MCP-1, an effect associated with ERK and p38 signaling pathway activation and with MMP9 secretion (Figure 5)
Summary
Cardiovascular disease is the leading cause of death worldwide. Peripheral arterial disease (PAD) is linked to a three- to six-fold increase in cardiovascular mortality compared to the general population [1,2,3]. Several studies have shown an improvement in patients’ health status after intramuscular injection of bone marrow- or peripheral blood-derived mononuclear cells [19,20,21] None of these trials showed efficient revascularization [22,23]. We showed that fucoidan significantly improved the beneficial effects of ECFC transplantation in a mouse model of hind limb ischemia, preventing tissue necrosis [30]. This tissue protection was associated with enhanced neoangiogenesis and a reduction in rhabdomyolysis. Fucoidan prestimulation enhanced each step of the angiogenic processes, namely cell recruitment to ischemic tissue via enhanced ECFC adhesion to activated endothelium, MMP-9 secretion, extravasation, and differentiation into a vascular network. We explored the signaling pathway involved in fucoidan-induced monocyte migration
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