Kristina Shkirkova, BSc
Reperfusion with mechanical thrombectomy and recombinant tissue plasminogen activator is a standard of care for patients with ischemic stroke. However, there is evidence from animal and clinical studies that the process of reperfusion contributes to vascular inflammation, secondary thrombosis and oxidative stress. The molecular mechanisms of this thrombo-inflammatory injury are not well understood.
The recent study by Dhanesha et al. published in Stroke examined the role of cellular fibronectin containing extra domain A (Fn-EDA) in thrombo-inflammatory injury. Fn-EDA is a glycoprotein that is present in a cellular form on the endothelial cells of the arteries and in a non-cellular form in the blood plasma. Previous studies have shown a significant elevation in the levels of plasma Fn-EDA in patients with cardiovascular disease. Additionally, severe vascular dysfunction in stroke is associated with increased expression of cellular Fn-EDA in activated endothelial cells. The aim of this study was to investigate contribution of plasma versus cellular Fn-EDA on stroke injury.
To make this study more clinically relevant, the authors chose to use an animal model with a comorbid condition of hyperlipidemia, which is a common risk factor in stroke patients. Two novel mouse strains were generated to determine the contribution of cellar and plasma Fn-EDA. The first strain combined plasma Fn-EDA deficiency in hepatocytes with a hyperlipidemic apolipoprotein E deficient background. The second strain combined endothelial cells Fn-EDA deficiency with a hyperlipidemic apolipoprotein E deficient background. To model focal cerebral ischemia utilizing novel mutant strains, this study used transient occlusion of the right middle cerebral artery via intraluminal monofilament insertion and via embolic artery occlusion with synthesized fibrin clots.
The results of the study showed that Fn-EDA in the plasma, but not in the endothelial cells, was essential for the exacerbation of stroke injury in a hyperlipidemic murine model. Lack of Fn-EDA in the plasma reduced post stroke mortality and improved sensorimotor behavioral recovery. Furthermore, there was an improvement in regional cerebral blood flow on laser speckle imaging, reduction in platelet and fibrinogen deposition, decreased neutrophil infiltration, and decline in TNFα and IL-1β expression in the infarct region in absence of plasma Fn-EDA. These results suggest that presence of Fn-EDA in the plasma promotes intracerebral thrombosis and post ischemic vascular inflammation. The authors conclude that targeting Fn-EDA specifically in the plasma may improve post stroke outcomes. But future studies are needed to verify these findings in other species and in older age, as well as in the presence of other comorbidities.
