Treatment of Mouse Limb Ischemia with an Integrative Hypoxia-Responsive Vector Expressing the Vascular Endothelial Growth Factor Gene

Autor(es)

Yasumura, Eduardo Gallatti ^[1] ; Stilhano, Roberta Sessa ^[1] ; Samoto, Vivian Yochiko ^[1] ; Matsumoto, Priscila Keiko ^[1] ; de Carvalho, Leonardo Pinto ^[1] ; Valero Lapchik, Valderez Bastos ^[1] ; Han, Sang Won ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Biophys, Res Ctr Gene Therapy, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 7, n. 3, p. e33944, 2012.
• Citações Web of Science: 9

Resumo

Constitutive vascular endothelial growth factor (VEGF) gene expression systems have been extensively used to treat peripheral arterial diseases, but most of the results have not been satisfactory. In this study, we designed a plasmid vector with a hypoxia-responsive element sequence incorporated into it with the phiC31 integrative system (pVHAVI) to allow long-term VEGF gene expression and to be activated under hypoxia. Repeated activations of VEGF gene expression under hypoxia were confirmed in HEK293 and C2C12 cells transfected with pVHAVI. In limb ischemic mice, the local administration of pVHAVI promoted gastrocnemius mass and force recovery and ameliorated limb necrosis much better than the group treated with hypoxia-insensitive vector, even this last group had produced more VEGF in muscle. Histological analyses carried out after four weeks of gene therapy showed increased capillary density and matured vessels, and reduced number of necrotic cells and fibrosis in pVHAVI treated group. By our study, we demonstrate that the presence of high concentration of VEGF in ischemic tissue is not beneficial or is less beneficial than maintaining a lower but sufficient and long-term concentration of VEGF locally. (AU)

• Processo FAPESP: 11/00859-6 - Papel do GM-CSF na reparação da lesão muscular: terapia gênica de lesões musculares
• Beneficiário: Sang Won Han
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 06/59630-0 - Terapia genica para isquemias cardiacas e de membros com vetores nao-virais.
• Beneficiário: Sang Won Han
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 08/52381-0 - Engenharia genética de um sistema de expressão duradoura e seletiva do VEGF (fator de crescimento endotelial vascular) para condição isquêmica baseados no sistema integrase ΦC31 e HRE (hypoxia response elemento): nova abordagem de terapia gênica para isquemia de membros
• Beneficiário: Eduardo Gallatti Yasumura
• Modalidade de apoio: Bolsas no Brasil - Mestrado