Cardioprotection was observed in the early and late phases of IPC; however, the enhanced mobilization and recruitment of BMSCs played an important role in the late phase of IPC.

Extracorporeal shock wave therapy promotes lymphangiogenesis and ameliorates secondary lymphedema, suggesting that extracorporeal shock wave therapy may be a novel, feasible, effective, and noninvasive treatment for lymphedema.

Cell-based angiogenesis is a promising method for the treatment of ischemic diseases, but the poor retention of implanted cells in targeted tissues is a major drawback. We tested whether hypoxic preconditioning increased retention and angiogenic potency of implanted cells in ischemic tissue. Hypoxic preconditioning of mouse peripheral blood mononuclear cells (PBMNCs) was done with 24 h of culture under 2% O(2). Normoxia-cultured PBMNCs were used as a control. Hypoxic preconditioning increased the adhesion capacity of the PBMNCs. Moreover, the expression of integrin alphaM and CXCR4 was significantly higher in the hypoxia-preconditioned PBMNCs than in the normoxia-cultured PBMNCs. Interestingly, the expression of intercellular adhesion molecule-1 (ICAM-1), a ligand of integrin alphaM, and stromal cell-derived factor-1 (SDF-1), a chemokine for CXCR4, were remarkably increased in the ischemic hindlimbs. The retention of the hypoxia-preconditioned PBMNCs was significantly higher than that of the normoxia-cultured PBMNCs, 3 days after their intramuscular implantation into ischemic hindlimbs. We also noted better blood flow in the ischemic hindlimbs implanted with the hypoxia-preconditioned PBMNCs than in those implanted with the normoxia-cultured PBMNCs, 14 days after treatment. Furthermore, antibody neutralization of integrin alphaM and CXCR4 abolished completely the increased cell retention and angiogenic potency of the hypoxia-preconditioned PBMNCs after implantation into the ischemic hindlimbs. These results indicate that hypoxic preconditioning of implanted cells is a feasible method of enhancing therapeutic angiogenesis by increasing their retention.

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Background : Cell-based angiogenesis is a promising treatment for ischemic diseases, but the poor retention of implanted cells in targeted tissue is a major drawback. We tested the hypothesis that hypoxic preconditioning increased retention and angiogenic potency of cells after implantation into ischemic tissues. Methods and Results : Peripheral blood mononuclear cells (PBMNCs) were isolated from C57BL/6 mice. Hypoxic preconditioning of PBMNCs was done by 24 hours of culture at 33°C in 2% O 2 . We used normoxia-cultured or freshly collected PBMNCs as controls. Compared with the normoxia-cultured PBMNCs, the hypoxia-preconditioned PBMNCs increased the adhesion capacity (75.1 ± 11.5/field vs. 39.7 ± 5.1/field, P<0.01). Furthermore, RT-PCR analysis showed that the expression of integrin μM and CXCR4 was significantly higher in the hypoxia-preconditioned PBMNCs than in the normoxia-cultured PBMNCs (P<0.05). Interestingly, immunohistochemistry revealed that the expression of ICAM-1, a ligand of integrin μM, and SDF-1, a chemokine for CXCR4, were remarkably increased in the ischemic hindlimbs. Three days after the intramuscular implantation into ischemic hindlimbs, the retention of the hypoxia-preconditioned PBMNCs (36.7 ± 4.2/field, P<0.01) was significantly higher than that of the normoxia-cultured (23.6 ± 1.3/field) or freshly collected PBMNCs (23.4 ± 2.6/field). We also noted higher microvessel density and better blood flow in the ischemic hindlimbs implanted with the hypoxia-preconditioned PBMNCs than in those implanted with the normoxia-cultured or freshly collected PBMNCs, 28 days after treatment; at 1023 ± 59/mm 2 vs. 767 ± 77/mm 2 and 775 ± 50/mm 2 , respectively (P<0.01) and 77.2 ± 5.5% vs. 63.6 ± 4.3% and 64.3 ± 2.5%, respectively (P<0.05) in the hypoxia, normoxia, and fresh groups. Conclusion : These results show that hypoxic preconditioning of PBMNCs is a feasible method of enhancing therapeutic angiogenesis by increasing their retention within ischemic tissues after implantation. Further studies are ongoing to elucidate whether the angiogenic potency of cells derived from the diseased animals is enhanced similarly to that of cells derived from healthy animals, after hypoxic preconditioning.

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