Extracellular Vimentin/VWF (von Willebrand Factor) Interaction Contributes to VWF String Formation and Stroke Pathology

Abstract

Background and Purpose: Von Willebrand factor (VWF) strings mediate spontaneous platelet adhesion in the vascular lumen, which may lead to microthrombi formation and contribute to stroke pathology. However, the mechanism of VWF string attachment at the endothelial surface is unknown. We tested the novel hypothesis that VWF strings are tethered to the endothelial surface through an interaction between extracellular vimentin and the A2 domain of VWF. We further explored the translational value of blocking this interaction in a model of ischemic stroke. Methods: Human endothelial cells (EC) and pressurized cerebral arteries were stimulated with histamine to elicit VWF string formation. Recombinant proteins and antibodies were employed to block VWF string formation. Mice underwent transient middle cerebral artery occlusion (MCAO) with reperfusion. Just prior to recanalization, mice were given either vehicle or A2 protein (recombinant VWF A2 domain) to disrupt the vimentin/VWF interaction. Laser speckle contrast imaging was used to monitor cortical perfusion. Results: Pressurized cerebral arteries produced VWF strings following histamine stimulation, which were reduced in arteries from vimentin knockout mice. VWF string formation was significantly reduced in EC incubated with A2 protein or anti-vimentin antibodies. Lastly, A2 protein treatment significantly improved cortical reperfusion following MCAO. Conclusions: We provide the first direct evidence of cerebral VWF strings and demonstrate that extracellular vimentin significantly contributes to VWF string formation via A2 domain binding. Lastly, we show that pharmacologically targeting the vimentin/VWF interaction through the A2 domain can promote improved reperfusion following ischemic stroke. Together, these studies demonstrate the critical role of VWF strings in stroke pathology and offer new therapeutic targets for treatment of ischemic stroke.

Vimentin as a Multifaceted Player and Potential Therapeutic Target in Viral Infections

“…In platelets, cell surface vimentin (CSV) has been involved in mediating adhesion at sites of injury by interaction with Von Willebrandt Factor (VWF) [45], reportedly through the tail domain. Pharmacological disruption of this interaction, either with anti-vimentin antibodies or with a VWF fragment, exerted beneficial effects in experimental models of ischemic stroke [60]. Vimentin exposed on HUVEC can interact with soluble CD44, allegedly through the head domain [44], whereas the C-terminal domain has been postulated to mediate the interaction of soluble vimentin with insulin-like growth factor 1 receptor (IGF-1R) [61].…”

Post-translational modifications of vimentin reflect different pathological processes associated with non-small cell lung cancer and chronic obstructive pulmonary disease

“…In the inflammatory setting, extracellular vimentin has been associated with various inflammatory states in different organs such as lupus erythematosus, pulmonary sarcoidosis, idiopathic pulmonary fibrosis and atherosclerosis [40][41][42][43]. In the vascular setting, extracellular vimentin has shown to be important in blood clotting via its contribution to Von Willebrand's factor string formation [44]. Furthermore, in wound healing, extracellular vimentin plays a role in the transition of mesenchymal cells to myofibroblasts, and in mice with spinal cord injury, vimentin induces axonal growth and increases motor function [45][46][47].…”

Development of barium‐based low viscosity contrast agents for micro CT vascular casting: Application to 3D visualization of the adult mouse cerebrovasculature

“…A silicone‐coated monofilament was introduced via the carotid artery into the CoW, where it blocked arterial flow at the origin of the MCA. This occlusion model, which is widely used in stroke research, promotes a decrease of 75% (or greater) in blood flow in the MCA territory and results in subsequent brain infarct (Fasipe et al, ; Liu & McCullough, ). Figure shows a comparison of the Microfil and BaSO 4 microparticle infusions with the monofilament in place.…”

“…The right MCA was occluded by placement of a silicone‐coated filament (5–6 mm coated length, Doccol) as we have described previously (Fasipe et al, ), but with the following modifications. Following occluder placement, the right common carotid artery and internal carotid artery were secured with sutures.…”