Publicação
Molecular mechanisms by which low doses of ionizing radiation promote neovascularization in ischemic tissues
| Resumo: | Peripheral arterial disease (PAD) is mainly caused by an obstructive artherosclerosis, which results in a mismatch between oxygen supply and demand. Diabetes is an important risk factor for PAD and it is present in almost 50% of the patients with limb ischemia. Critical limb ischemia (CLI) is the end stage of PAD, being characterized by severe obstruction of blood flow to the affected extremity, which results in ischemic rest pain, ulcers or gangrene. Despite substantial evidence of their efficacy in preclinical studies, as well as some promising phase I/II clinical trials, larger randomized clinical trials on angiogenic therapies for CLI have been unsatisfactory. Here, we investigated the ability of low-dose ionizing radiation (LDIR) to stimulate therapeutic neovascularization, in murine models, in a context of hindlimb ischemia (HLI), conjugated or not with diabetes. We demonstrate that 0.3 Gy, administered for four consecutive days, significantly improves blood perfusion in the murine ischemic limb by stimulating angiogenesis and arteriogenesis, as assessed by laser Doppler flow, capillary density and collateral vessel formation. LDIR significantly increased the circulating levels of VEGF, PlGF and G-CSF, as well as the number of circulating endothelial progenitor cells (EPCs), mediating their incorporation into ischemic muscles. These effects were dependent upon LDIR exposition on the ischemic niche (thigh and shank regions). In irradiated ischemic muscles, these effects were independent of the recruitment of monocytes and macrophages. Also, the vasculature in an irradiated non-ischemic bed was not affected and after 52-week LDIR exposure no differences in the incidence of morbidity and mortality were seen. Additionally, in diabetic mice, our data suggest that 0.3 Gy applied during four consecutive days significantly promote blood perfusion, capillary and collateral vessel densities in response to HLI induction. These findings disclose an innovative and non-invasive strategy to induce therapeutic angiogenesis in a murine model of severe HLI, emerging as a novel approach in the treatment of CLI. |
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| Autores principais: | Oliveira, Paula Alexandra Gomes de, 1981- |
| Assunto: | Neovascularização Radiação ionizante Isquémia do membro inferior Células endoteliais progenitoras Diabetes Teses de doutoramento - 2017 |
| Ano: | 2017 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Peripheral arterial disease (PAD) is mainly caused by an obstructive artherosclerosis, which results in a mismatch between oxygen supply and demand. Diabetes is an important risk factor for PAD and it is present in almost 50% of the patients with limb ischemia. Critical limb ischemia (CLI) is the end stage of PAD, being characterized by severe obstruction of blood flow to the affected extremity, which results in ischemic rest pain, ulcers or gangrene. Despite substantial evidence of their efficacy in preclinical studies, as well as some promising phase I/II clinical trials, larger randomized clinical trials on angiogenic therapies for CLI have been unsatisfactory. Here, we investigated the ability of low-dose ionizing radiation (LDIR) to stimulate therapeutic neovascularization, in murine models, in a context of hindlimb ischemia (HLI), conjugated or not with diabetes. We demonstrate that 0.3 Gy, administered for four consecutive days, significantly improves blood perfusion in the murine ischemic limb by stimulating angiogenesis and arteriogenesis, as assessed by laser Doppler flow, capillary density and collateral vessel formation. LDIR significantly increased the circulating levels of VEGF, PlGF and G-CSF, as well as the number of circulating endothelial progenitor cells (EPCs), mediating their incorporation into ischemic muscles. These effects were dependent upon LDIR exposition on the ischemic niche (thigh and shank regions). In irradiated ischemic muscles, these effects were independent of the recruitment of monocytes and macrophages. Also, the vasculature in an irradiated non-ischemic bed was not affected and after 52-week LDIR exposure no differences in the incidence of morbidity and mortality were seen. Additionally, in diabetic mice, our data suggest that 0.3 Gy applied during four consecutive days significantly promote blood perfusion, capillary and collateral vessel densities in response to HLI induction. These findings disclose an innovative and non-invasive strategy to induce therapeutic angiogenesis in a murine model of severe HLI, emerging as a novel approach in the treatment of CLI. |
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