Vascular oxidant stress enhances progression and angiogenesis of experimental atheroma
Vascular oxidant stress enhances progression and angiogenesis of experimental atheroma
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DOI：
10.1161/01.cir.0000109698.70638.2b
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发表时间：
2004-02-03
期刊：
影响因子：
37.8
通讯作者：
Galis, ZS
中科院分区：
文献类型：
--
作者：
Khatri, JJ;Johnson, C;Galis, ZS
背景-虽然多种病理过程与氧化应激有关，但氧化应激和动脉病变进展之间的因果关系仍不清楚。方法和结果-为了测试产生动脉壁氧化应激的效果，我们比较了野生型（WT）和转基因小鼠中血流停止诱导的小鼠颈动脉病变的进展（Tg（p22 vsmc）），其中p22 phox（NAD（P）H氧化酶的关键组分）的过表达靶向平滑肌细胞（SMC）。与WT小鼠相比，Tg（p22 vsmc）小鼠的动脉病变显著增大（P < 0.001），并且在所有检查的时间点均显示过氧化氢（H2 O2）和血管内皮生长因子（VEGF）水平升高（P < 0.001，每个时间点n = 4只动物），可能与Tg（p22 vsmc）动脉中通过SMC氧化应激增加缺氧诱导因子（HIF）-1 α表达有关，（203 +/- 12%相对于WT，P < 0.001，n = 3）和病变形成后。有趣的是，Tgp 22 vsmc病变并发广泛的新生内膜血管生成。体外实验证实，从Tg（p22 vsmc）分离的SMC是增加H2 O2，VEGF和HIF-1 α的来源，当与内皮细胞共培养时，它们诱导血管生成索状结构的能力。抗氧化剂依布硒啉抑制SMC的活动在体外和intralesion血管生成和病变progressioninvivo.Conclusions -我们已经证明了一种新的途径，氧化应激可以触发在体内的血管生成开关与实验斑块进展和血管生成。该通路可能与斑块内出血导致的人类动脉粥样硬化进展和不稳定有关。
Background - Although multiple pathological processes have been associated with oxidative stress, the causative relation between oxidative stress and arterial lesion progression remains unclear.Methods and Results - To test the effect of creating arterial wall oxidative stress, we compared progression of mouse carotid lesions induced by flow cessation in the wild-type (WT) versus transgenic mice (Tg(p22vsmc)), in which overexpression of p22phox, a critical component of NAD(P) H oxidase was targeted to smooth muscle cell (SMC). Compared with WT mice, arterial lesions grew significantly larger in Tg(p22vsmc) ( P < 0.001) and demonstrated elevated hydrogen peroxide (H2O2) and vascular endothelial growth factor ( VEGF) levels at all time points examined ( P < 0.001, n = 4 animals per time point), probably related to increased expression of hypoxia inducible factor (HIF)-1alpha via SMC oxidative stress in the Tg(p22vsmc) arteries, both basally (203 +/- 12% versus WT, P < 0.001, n = 3) and after lesion formation. Interestingly, Tgp22vsmc lesions were complicated by extensive neointimal angiogenesis. In vitro experiments confirmed SMCs isolated from Tg(p22vsmc) to be the source for increased H2O2, VEGF, and HIF-1 alpha and their capacity to induce angiogenic cord-like structures when cocultured with endothelial cells. The antioxidant ebselen inhibited SMC activities in vitro and intralesion angiogenesis and lesion progression in vivo.Conclusions - We have demonstrated a novel pathway by which oxidative stress can trigger in vivo an angiogenic switch associated with experimental plaque progression and angiogenesis. This pathway may be related to human atheroma progression and destabilization through intraplaque hemorrhage.