Vascular oxidant stress enhances progression and angiogenesis of experimental atheroma.

Khatri JJ, Johnson C, Magid R, Lessner SM, Laude KM, Dikalov SI, Harrison DG, Sung HJ, Rong Y, Galis ZS
Circulation. 2004 109 (4): 520-5

PMID: 14744973 · DOI:10.1161/01.CIR.0000109698.70638.2B

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, 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.

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.

MeSH Terms (19)

Animals Antioxidants Arteriosclerosis Azoles Carotid Artery Diseases Disease Progression Hydrogen Peroxide Membrane Transport Proteins Mice Mice, Transgenic Muscle, Smooth, Vascular NADPH Dehydrogenase NADPH Oxidases Neovascularization, Pathologic Organoselenium Compounds Oxidative Stress Phosphoproteins Reactive Oxygen Species Vascular Endothelial Growth Factor A

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