Ultrasound stimulation restores impaired neovascularization-related capacities of human circulating angiogenic cells

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Aims:Unsatisfactory effects of therapeutic angiogenesis in critical limb ischaemia may be ascribed to use of circulating angiogenic cells (CACs) derived from atherosclerotic patients with impaired neovascularization-related capacities. We tested whether ultrasound cell stimulation can restore the impaired capacities.Methods and results:During culture of human peripheral blood-derived mononuclear cells for 4 days to achieve CACs, we stimulated the cells in culture daily with low-intensity pulsed ultrasound stimulation (LIPUS). Application of LIPUS to cells in culture derived from healthy volunteers augmented the generation and migration capacities of CACs, increased concentrations of angiopoietin 2 and nitrogen oxides in the culture medium, and increased the expression of phosphorylated-Akt and endothelial nitric oxide synthase in CACs on western blotting. Application of LIPUS to cells in culture derived from atherosclerotic patients also augmented the generation and migration caacities of CACs. Although neovascularization in the ischaemic hindlimb of athymic nude mice was impaired after intramuscular injection of CACs derived from atherosclerotic patients compared with that using CACs derived from healthy volunteers, LIPUS of the cells in culture derived from atherosclerotic patients restored theneovascularization capacities. Conclusion:Therapeutic angiogenesis with LIPUS-pre-treated CACs may be a new strategy to rescue critical limb ischaemia in atherosclerotic patients.