Abstract
Background: Fibronectin-splicing variant containing extra domain A (Fn-EDA) is expressed in the endothelium of atherosclerotic arteries and elevated in circulation in at risk of patients with diabetes, hypertension, and atherosclerosis. Recent studies suggest that Fn-EDA contributes to ischemic stroke. The relative contribution of plasma versus (vs.) tissue Fn-EDA in stroke outcome remains unclear. We determined the contribution of plasma vs. tissue Fn- EDA in stroke exacerbation in the comorbid condition of hyperlipidemia. Methods: We generated Fn-EDA fl/fl AlbCre + , which express Fn-EDA in all tissues but not in plasma, on hyperlipidemic apolipoprotein E deficient ( Apoe -/- ) background. Controls were Fn- EDA fl/fl Apoe -/- mice, which express FN-EDA in all tissues and plasma. Susceptibility to stroke outcome was evaluated in male and female mice (8-10 weeks) by transient 1-hour ischemia followed by 1, 3, and 7 days of reperfusion. Quantitative assessment of stroke outcome was evaluated by measuring infarct volume (MRI), cerebral blood flow (laser speckle imaging), neurological outcome, and postischemic thrombo-inflammation (fibrin deposition, neutrophil, and inflammatory cytokines within the infarcted and surrounding region by Western blotting and immunohistochemistry). Susceptibility to thrombosis was evaluated in a FeCl 3 injury- induced carotid thrombosis model. Results: Irrespective of gender, Fn-EDA fl/fl AlbCre + Apoe -/- exhibited smaller infarcts and improved neurological outcome at days 1, 3 and 7 concomitant with improved survival, and decreased post ischemic thrombo-inflammation ( P <0.05 vs. Fn-EDA fl/fl Apoe -/- ). Laser speckle imaging revealed improved regional cerebral blood flow in Fn- DA fl/fl AlbCre + Apoe -/- mice ( P <0.05 vs. Fn-EDA fl/fl Apoe -/- ), suggesting that Fn-EDA present in plasma may promote intracerebral thrombosis and thereby exacerbate stroke. Using i ntravital microscopy, we found that Fn-EDA fl/fl AlbCre + Apoe -/- mice were less susceptible to experimental thrombosis ( P <0.05 vs. Fn-EDA fl/fl Apoe -/- ). Conclusion: Following STAIR guidelines, we provide evidence that Fn-EDA present in the plasma, but not tissue, contribute to stroke exacerbation by promoting thrombo-inflammation.
Published Version
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