A hypoxic inducible factor-1α hybrid enhances collateral development and reduces vascular leakage in diabetic rats
A hypoxic inducible factor-1α hybrid enhances collateral development and reduces vascular leakage in diabetic rats
复制标题
DOI：
10.1002/jgm.1318
复制
发表时间：
2009-05-01
影响因子：
3.5
通讯作者：
Jiang, Canwen
中科院分区：
文献类型：
--
作者：
Kajiwara, Hidetoshi;Luo, Zhengyu;Jiang, Canwen
背景 糖尿病是动脉粥样硬化的常见合并症。缺氧诱导因子 1 (HIF-1) 是缺氧血管生成反应的主要调节因子。方法我们研究了表达组成型活性 HIF-1 α 杂合体 (Ad2/HIF-1 α/VP16) 或血管内皮生长因子 (Ad2/VEGF) 的腺病毒载体对糖尿病大鼠后肢缺血模型侧枝发育和血管渗漏的影响。通过 Taqman 逆转录酶聚合酶链式反应测量，在 Zucker 瘦 (ZL) 大鼠中，小腿肌肉中 VEGF、血管生成素-1 和血管生成素-4 的 mRNA 水平短暂升高，而 Zucker 糖尿病肥胖 (ZDF) 大鼠则没有。术后 35 天，ZDF 动物的血管造影评分（根据死后血管造影确定）显着低于 ZL 动物。在单独的动物中，与 Ad2/CMVEV（不表达转基因的载体）或媒介物相比，将 Ad2/HIF-1a/VP16 和 Ad/2VEGF 肌肉注射到大腿肌肉中，注射后 21 天和 35 天的血管造影评分和毛细血管密度显着增加。注射 Ad2/CMVEV 或媒介物后，ZDF 大鼠大腿肌肉中的伊文思蓝染料含量显着高于 ZL 大鼠。 Ad2/HIF-1 α/VP16 但 Ad2/VEGF 不会降低组织伊文思蓝染料含量。结论 ZDF 大鼠对缺血的内源性血管生成反应受损，可能是由于血管生成因子的下调。 Ad2/HIF-1 α/VP16 增强 ZDF 大鼠缺血后肢的侧支发育并减少血管渗漏，表明混合 HIF-1 α 血管生成疗法可能对糖尿病合并症的外周血管疾病有效。版权所有 (C) 2009 John Wiley & Sons, Ltd.
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.Metbods 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. Copyright (C) 2009 John Wiley & Sons, Ltd.