Fn-EDA (Fibronectin Containing Extra Domain A) in the Plasma, but Not Endothelial Cells, Exacerbates Stroke Outcome by Promoting Thrombo-Inflammation

Nirav Dhanesha; Mehul R. Chorawala; Manish Jain; Abhinav Bhalla; Daniel Thedens; Manasa Nayak; Prakash Doddapattar; Anil K. Chauhan

doi:10.1161/STROKEAHA.118.023697

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Fn-EDA (Fibronectin Containing Extra Domain A) in the Plasma, but Not Endothelial Cells, Exacerbates Stroke Outcome by Promoting Thrombo-Inflammation

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Fn-EDA (Fibronectin Containing Extra Domain A) in the Plasma, but Not Endothelial Cells, Exacerbates Stroke Outcome by Promoting Thrombo-Inflammation

Nirav Dhanesha, Mehul R. Chorawala, Manish Jain, Abhinav Bhalla, Daniel Thedens, Manasa Nayak, Prakash Doddapattar and Anil K. Chauhan

Stroke (1970), Vol.50(5), pp.1201-1209

05/01/2019

DOI: 10.1161/STROKEAHA.118.023697

PMCID: PMC6476677

PMID: 30909835

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Abstract

Background and Purpose-Cellular Fn-EDA (fibronectin containing extra domain A) is expressed in activated endothelial cells and elevated in circulation in patients with cardiovascular diseases. Although global deficiency of Fn-EDA in mice improves stroke outcome, the specific contribution of plasma versus endothelium Fn-EDA in stroke outcome is currently unknown. We investigated the role of plasma versus endothelial Fn-EDA in stroke exacerbation in the comorbid condition of hyperlipidemia. Methods-We generated novel plasma Fn-EDA(-/-) (Fn-EDA(fl/fl)Alb(Cre)) and endothelial Fn-EDA(-/-) (Fn-EDA(fl/fl)Tie2(Cre)) strains on hyperlipidemic apolipoprotein E-deficient (ApoE(-/-)) background. By following the Stroke Therapy Academic Industry Roundtable guidelines, we evaluated stroke outcome in male and female mice. Susceptibility to ischemia/reperfusion injury was evaluated in 2 different models of stroke: intraluminal monofilament and embolic model on days 1, 3, and 7. Quantitative assessment of stroke outcome was evaluated by measuring infarct volume (by magnetic resonance imaging), cerebral blood flow (by laser speckle imaging), neurological and sensory-motor outcome, and postischemic thromboinflammation (platelet thrombi, fibrin, neutrophil, phospho-NF kappa B [nuclear factor kappa B], TNF alpha [tumor necrosis factor alpha], and IL1 beta [interleukin 1 beta]). Results-Stroke outcome was comparable in ApoE(-/-) Fn-EDA(fl/fl)Tie2(Cre) and control ApoE(-/-) Fn-EDA(fl/fl) mice suggesting endothelial Fn-EDA does not contribute to stroke. ApoE(-/-)Fn-EDA(fl/fl)Alb(Cre) mice exhibited significantly smaller infarcts and improved neurological and sensory-motor outcome at days 1, 3, and 7 in monofilament and embolic models of stroke. Improved stroke outcome was concomitant with enhanced survival, and decreased postischemic thrombo-inflammatory response (P<0.05 versus ApoE(-/-)Fn-EDA(fl/fl)). No sex-based differences were observed. Laser speckle imaging revealed significantly improved regional cerebral blood flow at 1 hour in ApoE(-/-)Fn-EDA(fl/fl)Alb(Cre) mice suggesting plasma Fn-EDA promotes postischemic secondary thrombosis. Coinfusion of anti-Fn-EDA antibody with r-tPA (recombinant tissue-type plasminogen activator) in ApoE(-/-)mice, 1 hour after embolization, improved stroke outcome with enhanced survival, and improved neurological outcome (P<0.05 versus r-tPA). Conclusions-Genetic evidence suggests that plasma Fn-EDA exacerbates stroke outcome by promoting postischemic thrombo-inflammation. Interventions targeting plasma Fn-EDA may reduce brain damage after reperfusion. Visual Overview-An online visual overview is available for this article.

Cardiovascular System & Cardiology

Clinical Neurology

Life Sciences & Biomedicine

Neurosciences & Neurology

Peripheral Vascular Disease

Science & Technology

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Title: Subtitle: Fn-EDA (Fibronectin Containing Extra Domain A) in the Plasma, but Not Endothelial Cells, Exacerbates Stroke Outcome by Promoting Thrombo-Inflammation
Creators: Nirav Dhanesha - University of Iowa
Mehul R. Chorawala - University of Iowa
Manish Jain - University of Iowa
Abhinav Bhalla - University of Iowa
Daniel Thedens - University of Iowa
Manasa Nayak - University of Iowa
Prakash Doddapattar - University of Iowa
Anil K. Chauhan - University of Iowa
Resource Type: Journal article
Publication Details: Stroke (1970), Vol.50(5), pp.1201-1209
DOI: 10.1161/STROKEAHA.118.023697
PMID: 30909835
PMCID: PMC6476677
NLM abbreviation: Stroke
ISSN: 0039-2499
eISSN: 1524-4628
Publisher: Lippincott Williams & Wilkins
Number of pages: 9
Grant note: R01 NS109910 / National Institute of Neurological Disorders and Stroke of the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) R35 HL139926 / National Heart, Lung and Blood Institute of the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) 17POST33650044 / American Heart Association 18EIA33900009 / Established Investigator Award from American Heart Association R01NS109910 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) R35HL139926 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
Language: English
Date published: 05/01/2019
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiology; Electrical and Computer Engineering; Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984359813902771

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