RESUMO
BACKGROUND: Diabetes mellitus is a common comorbidity of atherosclerosis. Hypoxia-inducible factor-1 (HIF-1) is the master regulator of the angiogenic response to hypoxia. METHODS: We studied the effects of adenoviral vectors expressing a constitutively active HIF-1 alpha hybrid (Ad2/HIF-1 alpha/VP16) or vascular endothelial growth factor (Ad2/VEGF) on collateral development and vascular leakiness in a diabetic rat model of hindlimb ischemia. RESULTS: After the removal of the right femoral artery, the mRNA levels of VEGF, angiopoietin-1 and angiopietin-4 in the calf muscles, as measured by Taqman reverse transcriptase-polymerase chain reaction, were transiently elevated in Zucker lean (ZL) but not Zucker diabetic fatty (ZDF) rats. The angiographic score, as determined by post-mortem angiography, was significantly lower in ZDF animals 35 days after surgery compared to their ZL counterparts. In separate animals, intramuscular injection of Ad2/HIF-1a/VP16 and Ad/2VEGF into the thigh muscles significantly increased the angiographic score and capillary density 21 and 35 days after the injection compared to Ad2/CMVEV (a vector expressing no transgene) or vehicle. After the injection of Ad2/CMVEV or vehicle, the Evans-blue dye content in the thigh muscles was significantly higher in ZDF rats than their ZL counterparts. Ad2/HIF-1 alpha/VP16 but not Ad2/VEGF reduced tissue Evans blue dye content. CONCLUSIONS: The endogenous angiogenic response to ischemia was impaired in ZDF rats, possibly due to down-regulation of angiogenic factors. Ad2/HIF-1 alpha/VP16 enhanced collateral development and reduced vascular leakage in the ischemic hindlimb of ZDF rats indicating that hybrid HIF-1 alpha angiogenic therapy may be efficacious for peripheral vascular disease with a diabetic comorbidity.
Assuntos
Vasos Sanguíneos/patologia , Circulação Colateral/fisiologia , Diabetes Mellitus Experimental/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Recombinantes/metabolismo , Adenoviridae/genética , Animais , Peso Corporal , DNA/genética , Artéria Femoral/cirurgia , Regulação da Expressão Gênica , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Hemoglobinas Glicadas/metabolismo , Membro Posterior/irrigação sanguínea , Imuno-Histoquímica , Injeções Intramusculares , Isquemia , Neovascularização Fisiológica/genética , Ratos , Ratos Zucker , TransgenesRESUMO
We experienced the perioperative management of the living related liver transplantation (LRLT) in a patient with hepatopulmonary syndrome (HPS). HPS is seen in 15% of patients of the endstage liver failure, and it accompanies the various types of hypoxia. The diagnostic standards of HPS are chronic liver disease usually complicated by portal hypertension with or without cirrhosis, arterial hypoxemia (PaO2 < 70 mmHg or A-aDO2 gradient > 20 mmHg), and intrapulmonary vascular dilation. The present case conformed to the diagnostic standard. But this case was of a mild type of HPS, because PaO2 was elevated after O2 inhalation and extrapulmonary uptake of 99mTcMAA after lung perfusion was lower than 40%. During perioperative period of LRLT, there were no complications such as hypoxia, acute rejection, bleeding and infection. Therefore HPS would be improved after LRLT. In the management of perioperative period it is important to be aware of hypoxia and to evaluate preoperatively the condition of the patient properly.