RESUMO
OBJECTIVE: The goal of this study was to test the contributing role of increasing glucose uptake in vascular smooth muscle cells (VSMCs) in vascular complications and disease. METHODS AND RESULTS: A murine genetic model was established in which glucose trasporter 1 (GLUT1), the non-insulin-dependent glucose transporter protein, was overexpressed in smooth muscle using the sm22α promoter. Overexpression of GLUT1 in smooth muscle led to significant increases in glucose uptake (n=3, P<0.0001) as measured using radiolabeled 2-deoxyglucose. Fasting blood glucose, insulin, and nonesterified fatty acids were unchanged. Contractility in aortic ring segments was decreased in sm22α-GLUT1 mice (n=10, P<0.04). In response to vascular injury, sm22α-GLUT1 mice exhibited a proinflammatory phenotype, including a significant increase in the percentage of neutrophils in the lesion (n=4, P<0.04) and an increase in monocyte chemoattractant protein-1 (MCP-1) immunofluorescence. Circulating haptoglobin and glutathione/total glutathione were significantly higher in the sm22α-GLUT1 mice postinjury compared with controls (n=4, P<0.05), suggesting increased flux through the pentose phosphate pathway. sm22α-GLUT1 mice exhibited significant medial hypertrophy following injury that was associated with a significant increase in the percentage of VSMCs in the media staining positive for nuclear phosphoSMAD2/3 (n=4, P<0.003). CONCLUSIONS: In summary, these findings suggest that increased glucose uptake in VSMCs impairs vascular contractility and accelerates a proinflammatory, neutrophil-rich lesion in response to injury, as well as medial hypertrophy, which is associated with enhanced transforming growth factor-ß activity.
Assuntos
Transportador de Glucose Tipo 1/metabolismo , Inflamação/etiologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Vasoconstrição , Animais , Aorta/metabolismo , Aorta/fisiopatologia , Glicemia/metabolismo , Células Cultivadas , Quimiocina CCL2/metabolismo , Desoxiglucose/metabolismo , Modelos Animais de Doenças , Ácidos Graxos não Esterificados/sangue , Artéria Femoral/lesões , Artéria Femoral/metabolismo , Transportador de Glucose Tipo 1/genética , Glutationa/sangue , Haptoglobinas/metabolismo , Humanos , Hipertrofia , Inflamação/metabolismo , Inflamação/patologia , Insulina/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas Musculares/genética , Músculo Liso Vascular/lesões , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/patologia , Infiltração de Neutrófilos , Fosforilação , Regiões Promotoras Genéticas , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Regulação para CimaRESUMO
Regulatory T cells (Tregs) are generated to antigens (Ag) found in the retina. Some Tregs are the result of ectopic expression of the retinal Ags in the thymus, where developing T cells are committed to enter the regulatory lineage. However, the generation of retinal Ag-specific Tregs independent of the thymus was uncertain. Our studies show that Tregs can be generated from mature, peripheral T cells based on exposure to retinal Ags. These peripherally induced Tregs limited immune responses and experimental autoimmune disease induced by retinal Ags and thus constitute a crucial component of retinal immune privilege.