RESUMO
BACKGROUND: Platelet-derived growth factor (PDGF) antagonists have demonstrated beneficial effects on neointima formation, but in studies using PDGF inhibitors and extended follow-up, the lesions reoccur. These findings implicate a need to combine targeting of PDGF with other strategies. Stimulation of reendothelialization by treatment with endothelial cell mitogens of the vascular endothelial growth factor (VEGF) family counteracts restenosis, but there are also concerns regarding the durability of the effect with this approach. METHODS AND RESULTS: To explore whether a combined use of PDGF antagonist and stimulation of reendothelialization confers better results than each therapy alone, we combined systemic administration of imatinib mesylate (STI571/Gleevec, 10 mg/kg(-1) per d(-1)), a tyrosine kinase inhibitor with activity against PDGF receptors, with local intravascular adenovirus-mediated VEGF-C gene transfer (1.15x10(10) pfu) in cholesterol-fed, balloon-injured rabbits. Throughout the course of the STI571 therapy, the circulating concentrations were able to suppress PDGF receptor phosphorylation. At 3 weeks, the treatment with STI571 led to a transient decrease in intralesion macrophages and to an increase in intimal smooth muscle cell apoptosis. VEGF-C application reduced neointima formation and accelerated reendothelialization. However, none of the therapies alone reduced intimal thickening at a 6-week time point, whereas the combined treatment led to a persistent reduction (55% versus control) in lesion size at this time point. CONCLUSIONS: Our study provides one of the first successful examples of gene therapy combined with a pharmacological treatment to modulate 2 distinct ligand-receptor signaling systems and suggests combination of local VEGF-C gene therapy with systemic inhibition of PDGF signaling as a novel principle to prevent intimal hyperplasia after vascular manipulations.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Hipercolesterolemia/terapia , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Túnica Íntima/patologia , Fator C de Crescimento do Endotélio Vascular/genética , Adenoviridae/genética , Administração Oral , Animais , Artérias , Benzamidas , Divisão Celular/efeitos dos fármacos , Movimento Celular , Terapia Combinada , Endotélio Vascular/patologia , Inibidores Enzimáticos/administração & dosagem , Técnicas de Transferência de Genes , Vetores Genéticos/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/patologia , Mesilato de Imatinib , Macrófagos/imunologia , Músculo Liso Vascular/patologia , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Coelhos , Túnica Íntima/citologia , Túnica Íntima/efeitos dos fármacos , Túnica Média/patologiaAssuntos
Linfocinas/imunologia , Nefrite Intersticial/imunologia , Nefrite Intersticial/patologia , Fator de Crescimento Derivado de Plaquetas/imunologia , Obstrução Ureteral/imunologia , Obstrução Ureteral/patologia , Animais , Anticorpos/farmacologia , Células Cultivadas , Quimiocina CCL2/genética , Fibroblastos/patologia , Fibrose , Rim/patologia , Rim/fisiologia , Linfocinas/genética , Linfocinas/metabolismo , Macrófagos/patologia , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Monócitos/patologia , Nefrite Intersticial/fisiopatologia , Neutrófilos/patologia , Fosforilação , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , Ratos , Receptores do Fator de Crescimento Derivado de Plaquetas/imunologia , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Ovinos , Linfócitos T/patologia , Obstrução Ureteral/fisiopatologiaRESUMO
Several platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) family members display C-terminal protein motifs that confer retention of the secreted factors within the pericellular space. To address the role of PDGF-B retention in vivo, we deleted the retention motif by gene targeting in mice. This resulted in defective investment of pericytes in the microvessel wall and delayed formation of the renal glomerulus mesangium. Long-term effects of lack of PDGF-B retention included severe retinal deterioration, glomerulosclerosis, and proteinuria. We conclude that retention of PDGF-B in microvessels is essential for proper recruitment and organization of pericytes and for renal and retinal function in adult mice.