Introduction: The aim here is to elucidate the mechanisms involved in post-stroke cerebrovascular impairments in metabolic syndrome (MetS) that pre-dispose obese patients to more severe post-stroke deficits.
Methods: 1 hr middle cerebral artery occlusion was performed in 17 week old lean (LZR) and obese Zucker (OZR: MetS model) rats. At 24 hr or 15 days post-stroke, the ipsilateral middle cerebral artery (MCA) was cannulated in an ex-vivo microvessel preparation to examine MCA reactivity. Cerebrovascular microvessel density (MVD) was examined 15 days post-stroke via IHC. To examine a potential role of Nox2 and oxidative stress, a specific inhibitor of Nox2 oxidase Nox2-dstat (i.p 10mg/kg) was given during the stroke procedure in OZR.
Results: In LZR, MCA reactivity was impaired vs. non-stroke control at 24hr post-stroke and remained stable at 15 days post-stroke. In LZR, NO bioavailability was reduced at 24hrs vs. controls, which remained stable at 15 days. In OZR, the MCA impairment was greater at 24 hr vs. LZR, and worsened significantly at 15 days post stroke. NO bioavailability for OZR at 24 hr was similar to LZR stroke, but by 15 days had fallen. MVD was reduced 15 days post-stroke, with a larger loss in OZR vs. LZR. Stroke mortality and infarct size were higher for OZR. Nox2 inhibition restored MCA reactivity, improved MVD and NO levels, and limited stroke infarct size in OZR post-stroke.
Discussion: Our data suggest that the MetS increases stroke severity and drives a progressive decline in cerebrovascular dysfunction following ischemic stroke. Inhibiting Nox2 production improved stroke outcome in MetS.