Adhesion of platelets to stimulated endothelium contributes to thrombotic events associated with arterial thrombosis and ischemic stroke. Although anti-platelet agents have reduced unfavorable outcomes, it is well appreciated that the risk for bleeding or recurrent thrombotic events persists. The pathophysiological function of the protein von Willebrand factor (VWF) in arterial thrombosis and stroke has been validated by experimental and clinical studies. VWF is important for mediating the tethering of the flowing platelets over the surface-bound VWF that result in platelet adhesion, activation, and aggregation ? and ultimately occlusion of the vessel. Recently, we described that vimentin expressed on the cell surface of platelets binds to VWF and contributes to platelet adhesion at high shear stress. We also have shown that a recombinant A2 domain of VWF (?A2 protein?) with binding activity for vimentin blocked the interaction between vimentin and VWF. Additional experiments employing endothelial cells (ECs), which also express vimentin on the cell surface, revealed that that A2 protein prevented the formation of ultra large (long) VWF multimers or VWF strings on normal ECs and failed to interact with vimentin-deficient ECs. Moreover, the large number of VWF strings observed at the endothelial surface of stimulated cerebral arteries from wild type (WT) mice contrast to the significantly less strings seen on arteries from vimentin deficient mice. These data demonstrate for the first time the presence of hyperadhesive VWF strings in the cerebrovasculature and the potential for these strings in cerebrovascular pathologies. Finally, injury-induced thrombus formation in distal middle cerebral artery (MCA) and severity of ischemic stroke was reduced in Vim(-/-) compared to WT mice. The central hypothesis of this application is that cell-surface expressed vimentin interacts with the A2 domain of VWF strings, thus contributing to anchoring of VWF strings to the stimulated endothelium and attachment to circulating platelets. This application also proposes to test the hypothesis that disrupting the vimentin/VWF interaction reduces thrombosis and further damage during ischemic reperfusion.
Three aims are proposed:
Aim 1) Define the essential sites in vimentin and VWF that are involved in the vimentin/VWF interaction on platelets and endothelial cells;
Aim 2) Determine the role of platelet and endothelial vimentin in thrombosis in vivo;
and Aim 3) Demonstrate therapeutic benefit of disrupting the vimentin-VWF interaction following stroke. Completion of these aims will impact public health by demonstrating a novel receptor for VWF, and will lay the foundation to test this new interaction as a therapeutic target to prevent arterial thrombosis and treat ischemic stroke.

Public Health Relevance

The role of platelet adhesion is to stop bleeding as well as to pathologically occlude vessels. Vimentin has been described as a novel ligand for Von Willebrand factor (VWF). This novel vimentin-VWF interaction may be relevant in mediating platelet adhesion to stimulated endothelium, causing heart attack, and stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS094280-02
Application #
9266834
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
2016-09-01
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$506,726
Indirect Cost
$187,025
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Fasipe, Titilope A; Hong, Sung-Ha; Da, Qi et al. (2018) Extracellular Vimentin/VWF (von Willebrand Factor) Interaction Contributes to VWF String Formation and Stroke Pathology. Stroke 49:2536-2540
Lam, Fong W; Da, Qi; Guillory, Bobby et al. (2018) Recombinant Human Vimentin Binds to P-Selectin and Blocks Neutrophil Capture and Rolling on Platelets and Endothelium. J Immunol 200:1718-1726
Valladolid, Christian; Yee, Andrew; Cruz, Miguel A (2018) von Willebrand Factor, Free Hemoglobin and Thrombosis in ECMO. Front Med (Lausanne) 5:228
Cao, Zhijuan; Balasubramanian, Adithya; Pedersen, Steen E et al. (2017) TRPV1-mediated Pharmacological Hypothermia Promotes Improved Functional Recovery Following Ischemic Stroke. Sci Rep 7:17685