Khatri Jaikirshan J, Johnson Chad, Magid Richard, Lessner Susan M, Laude Karine M, Dikalov Sergey I, Harrison David G, Sung Hak-Joon, Rong Yuan, Galis Zorina S
Division of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Circulation. 2004 Feb 3;109(4):520-5. doi: 10.1161/01.CIR.0000109698.70638.2B. Epub 2004 Jan 26.
Although multiple pathological processes have been associated with oxidative stress, the causative relation between oxidative stress and arterial lesion progression remains unclear.
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, Tg(p22vsmc) 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-1alpha 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.
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.
尽管多种病理过程与氧化应激相关，但氧化应激与动脉病变进展之间的因果关系仍不清楚。
为了测试产生动脉壁氧化应激的作用，我们比较了野生型（WT）小鼠与转基因小鼠（Tg(p22vsmc)）中因血流停止诱导的颈动脉病变进展情况，在转基因小鼠中，NAD(P)H氧化酶的关键成分p22phox的过表达靶向平滑肌细胞（SMC）。与WT小鼠相比，Tg(p22vsmc)小鼠的动脉病变显著增大（P<0.001），并且在所有检测时间点过氧化氢（H2O2）和血管内皮生长因子（VEGF）水平均升高（P<0.001，每个时间点n = 4只动物），这可能与Tg(p22vsmc)动脉中通过SMC氧化应激导致的缺氧诱导因子（HIF）-1α表达增加有关，无论是在基础状态（203±12% 对比WT，P<0.001，n = 3）还是病变形成后。有趣的是，Tg(p22vsmc)病变伴有广泛的新生内膜血管生成。体外实验证实，从Tg(p22vsmc)分离的SMC是H2O2、VEGF和HIF-1α增加的来源，并且当与内皮细胞共培养时它们具有诱导血管生成索状结构的能力。抗氧化剂依布硒仑在体外抑制SMC活性以及体内病变内血管生成和病变进展。
我们已经证明了一种新的途径，通过该途径氧化应激可在体内触发与实验性斑块进展和血管生成相关的血管生成开关。该途径可能与人类动脉粥样硬化进展以及通过斑块内出血导致的斑块不稳定有关。
