Endothelial Cell-Derived von Willebrand Factor Is the Major Determinant That Mediates von Willebrand Factor-Dependent Acute Ischemic Stroke by Promoting Postischemic Thrombo-Inflammation

Nirav Dhanesha; Prem Prakash; Prakash Doddapattar; Ira Khanna; Molly J Pollpeter; Manasa K Nayak; Janice M Staber; Anil K Chauhan

doi:10.1161/ATVBAHA.116.307660

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Endothelial Cell-Derived von Willebrand Factor Is the Major Determinant That Mediates von Willebrand Factor-Dependent Acute Ischemic Stroke by Promoting Postischemic Thrombo-Inflammation

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Endothelial Cell-Derived von Willebrand Factor Is the Major Determinant That Mediates von Willebrand Factor-Dependent Acute Ischemic Stroke by Promoting Postischemic Thrombo-Inflammation

Nirav Dhanesha, Prem Prakash, Prakash Doddapattar, Ira Khanna, Molly J Pollpeter, Manasa K Nayak, Janice M Staber and Anil K Chauhan

Arteriosclerosis, thrombosis, and vascular biology, Vol.36(9), pp.1829-1837

09/2016

DOI: 10.1161/ATVBAHA.116.307660

PMCID: PMC5001895

PMID: 27444201

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Abstract

von Willebrand factor (VWF), which is synthesized in endothelial cells and megakaryocytes, is known to worsen stroke outcome. In vitro studies suggest that platelet-derived VWF (Plt-VWF) is biochemically different from the endothelial cell-derived VWF (EC-VWF). However, little is known about relative contribution of different pools of VWF in stroke. Using bone marrow transplantation, we generated chimeric Plt-VWF mice, Plt-VWF mice that lack ADAMTS13 in platelets and plasma (Plt-VWF/Adamts13(-/-)), and EC-VWF mice to determine relative contribution of different pools of VWF in stroke. In brain ischemia/reperfusion injury model, we found that infarct size and postischemic intracerebral thrombo-inflammation (fibrin(ogen) deposition, neutrophil infiltration, interleukin-1β, and tumor necrosis factor-α levels) within lesions were comparable between EC-VWF and wild-type mice. Infarct size and postischemic thrombo-inflammation were comparable between Plt-VWF and Plt-VWF/Adamts13(-/-) mice, but decreased compared with EC-VWF and wild-type mice (P<0.05) and increased compared with Vwf(-/-) mice (P<0.05). Susceptibility to FeCl3 injury-induced carotid artery thrombosis was comparable between wild-type and EC-VWF mice, whereas Plt-VWF and Plt-VWF/Adamts13(-/-) mice exhibited defective thrombosis. Although most of the injured vessels did not occlude, slope over time showed that thrombus growth rate was increased in both Plt-VWF and Plt-VWF/Adamts13(-/-) mice compared with Vwf(-/-) mice (P<0.05), but decreased compared with wild-type or EC-VWF mice. Plt-VWF, either in presence or absence of ADAMTS13, partially contributes to VWF-dependent injury and postischemic thrombo-inflammation after stroke. EC-VWF is the major determinant that mediates VWF-dependent ischemic stroke by promoting postischemic thrombo-inflammation.

Mesenteric Vascular Occlusion - metabolism

Inflammation - pathology

Thrombosis - chemically induced

Carotid Artery Diseases - chemically induced

Male

von Willebrand Factor - genetics

Mesenteric Vascular Occlusion - genetics

Infarction, Middle Cerebral Artery - metabolism

Neutrophil Infiltration

Inflammation - metabolism

Time Factors

Carotid Artery Diseases - pathology

Lasers

Chlorides

Bone Marrow Transplantation

Infarction, Middle Cerebral Artery - genetics

Inflammation Mediators - metabolism

Carotid Artery Diseases - metabolism

Reperfusion Injury - genetics

Reperfusion Injury - metabolism

Disease Models, Animal

von Willebrand Factor - metabolism

Genetic Predisposition to Disease

Reperfusion Injury - pathology

Signal Transduction

Endothelial Cells - metabolism

Platelet Transfusion

Mice, Inbred C57BL

Infarction, Middle Cerebral Artery - pathology

Mice, Knockout

Ferric Compounds

Thrombosis - pathology

Phenotype

Thrombosis - metabolism

Animals

Mesenteric Vascular Occlusion - pathology

Blood Platelets - metabolism

ADAMTS13 Protein - genetics

Carotid Artery Diseases - genetics

Inflammation - genetics

ADAMTS13 Protein - deficiency

Thrombosis - genetics

Details

Title: Subtitle: Endothelial Cell-Derived von Willebrand Factor Is the Major Determinant That Mediates von Willebrand Factor-Dependent Acute Ischemic Stroke by Promoting Postischemic Thrombo-Inflammation
Creators: Nirav Dhanesha - From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City
Prem Prakash - From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City
Prakash Doddapattar - From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City
Ira Khanna - From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City
Molly J Pollpeter - From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City
Manasa K Nayak - From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City
Janice M Staber - From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City
Anil K Chauhan - From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City. anil-chauhan@uiowa.edu
Resource Type: Journal article
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.36(9), pp.1829-1837
Publisher: United States
DOI: 10.1161/ATVBAHA.116.307660
PMID: 27444201
PMCID: PMC5001895
ISSN: 1079-5642
eISSN: 1524-4636
Grant note: R01 HL118246 / NHLBI NIH HHS R01 HL118742 / NHLBI NIH HHS
Language: English
Date published: 09/2016
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Hematology/Oncology; Internal Medicine
Record Identifier: 9984070729402771

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