Yan Jinglian, Tie Guodong, Park Brian, Yan Yagai, Nowicki Philip T, Messina Louis M
Department of Surgery, University of Massachusetts Medical School, Worcester, Mass 01655, USA.
J Vasc Surg. 2009 Dec;50(6):1412-22. doi: 10.1016/j.jvs.2009.08.007. Epub 2009 Oct 17.
We sought to directly compare the effects of type 1 and type 2 diabetes on postischemic neovascularization and evaluate the mechanisms underlying differences between these groups. We tested the hypothesis that type 2 diabetic mice have a greater reduction in endothelial nitric oxide synthase (eNOS) expression, a greater increase in oxidative stress, and reduced arteriogenesis and angiogenesis, resulting in less complete blood flow recovery than type 1 diabetic mice after induction of hind limb ischemia.
Hind limb ischemia was generated by femoral artery excision in streptozotocin-treated mice (model of type 1 diabetes), in Lepr(db/db) mice (model of type 2 diabetes), and in control (C57BL/6) mice. Dependent variables included eNOS expression and markers of arteriogenesis, angiogenesis, and oxidative stress.
Postischemia recovery of hind limb perfusion was significantly less in type 2 than in type 1 diabetic mice; however, neither group demonstrated a significant increase in collateral artery diameter or collateral artery angioscore in the ischemic hind limb. The capillary/myofiber ratio in the gastrocnemius muscle decreased in response to ischemia in control or type 1 diabetic mice but remained the same in type 2 diabetic mice. Gastrocnemius muscle eNOS expression was lower in type 1 and 2 diabetic mice than in control mice. This expression decreased after induction of ischemia in type 2 but not in type 1 diabetic mice. The percentage of endothelial progenitor cells (EPC) in the peripheral blood failed to increase in either diabetic group after induction of ischemia, whereas this variable significantly increased in the control group in response to ischemia. EPC eNOS expression decreased after induction of ischemia in type 1 but not in type 2 diabetic mice. EPC nitrotyrosine accumulation increased after induction of ischemia in type 2 but not in type 1 diabetic mice. EPC migration in response to vascular endothelial growth factor was reduced in type 1 and type 2 diabetic mice vs control mice. EPC incorporation into tubular structures was less effective in type 2 diabetic mice. Extensive fatty infiltration was present in ischemic muscle of type 2 but not in type 1 diabetic mice.
Type 2 diabetic mice displayed a significantly less effective response to hind limb ischemia than type 1 diabetic mice.
我们试图直接比较1型和2型糖尿病对缺血后新生血管形成的影响，并评估两组之间差异的潜在机制。我们检验了以下假设：与1型糖尿病小鼠相比，2型糖尿病小鼠内皮型一氧化氮合酶（eNOS）表达降低幅度更大，氧化应激增加幅度更大，动脉生成和血管生成减少，导致后肢缺血诱导后血流恢复不完全。
通过切除链脲佐菌素处理的小鼠（1型糖尿病模型）、Lepr（db/db）小鼠（2型糖尿病模型）和对照（C57BL/6）小鼠的股动脉来诱导后肢缺血。因变量包括eNOS表达以及动脉生成、血管生成和氧化应激的标志物。
2型糖尿病小鼠后肢灌注的缺血后恢复明显低于1型糖尿病小鼠；然而，两组在缺血后肢的侧支动脉直径或侧支动脉血管评分均未显示出显著增加。对照组或1型糖尿病小鼠的腓肠肌中毛细血管/肌纤维比值因缺血而降低，但2型糖尿病小鼠则保持不变。1型和2型糖尿病小鼠腓肠肌中的eNOS表达均低于对照小鼠。这种表达在2型糖尿病小鼠缺血诱导后降低，但在1型糖尿病小鼠中未降低。缺血诱导后，两组糖尿病小鼠外周血中内皮祖细胞（EPC）的百分比均未增加，而对照组中该变量因缺血而显著增加。1型糖尿病小鼠缺血诱导后EPC的eNOS表达降低，但2型糖尿病小鼠未降低。2型糖尿病小鼠缺血诱导后EPC硝基酪氨酸积累增加，但1型糖尿病小鼠未增加。与对照小鼠相比，1型和2型糖尿病小鼠中EPC对血管内皮生长因子的迁移反应降低。2型糖尿病小鼠中EPC整合到管状结构中的效果较差。2型糖尿病小鼠的缺血肌肉中存在广泛的脂肪浸润，而1型糖尿病小鼠中则没有。
与1型糖尿病小鼠相比，2型糖尿病小鼠对后肢缺血的反应明显较差。
