Vascular Oxidant Stress Enhances Progression and Angiogenesis of Experimental Atheroma

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Abstract
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 (Tgp22vsmc), 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 Tgp22vsmc (P2O2) and vascular endothelial growth factor (VEGF) levels at all time points examined (Pp22vsmc arteries, both basally (203±12% versus WT, Pp22vsmc lesions were complicated by extensive neointimal angiogenesis. In vitro experiments confirmed SMCs isolated from Tgp22vsmc to be the source for increased H2O2, VEGF, and HIF-1α 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.

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