Low-density lipoprotein promotes microvascular thrombosis by enhancing von Willebrand factor self-association.

Abstract

von Willebrand factor (VWF) mediates primary hemostasis and thrombosis in response to hydrodynamic forces. We previously showed that high shear promoted self-association of VWF into hyperadhesive strands, which can be attenuated by high-density lipoprotein (HDL) and apolipoprotein A-I. In this study, we show that low-density lipoprotein (LDL) binds VWF under shear and enhances self-association. Vortexing VWF in tubes resulted in its loss from the solution and deposition onto tube surfaces, which was prevented by HDL. At a stabilizing HDL concentration of 1.2 mg/mL, increasing concentrations of LDL progressively increased VWF loss, the effect correlating with the LDL-to-HDL ratio and not the absolute concentration of the lipoproteins. Similarly, HDL diminished deposition of VWF in a post-in-channel microfluidic device, whereas LDL increased both the rate and extent of strand deposition, with both purified VWF and plasma. Hypercholesterolemic human plasma also displayed accelerated VWF accumulation in the microfluidic device. The initial rate of accumulation correlated linearly with the LDL-to-HDL ratio. In Adamts13-/- and Adamts13-/-LDLR-/- mice, high LDL levels enhanced VWF and platelet adhesion to the myocardial microvasculature, reducing cardiac perfusion, impairing systolic function, and producing early signs of cardiomyopathy. In wild-type mice, high plasma LDL concentrations also increased the size and persistence of VWF-platelet thrombi in ionophore-treated mesenteric microvessels, exceeding the accumulation seen in similarly treated ADAMTS13-deficient mice that did not receive LDL infusion. We propose that targeting the interaction of VWF with itself and with LDL may improve the course of thrombotic microangiopathies, atherosclerosis, and other disorders with defective microvascular circulation.

• Authors: Dominic W Chung, Kimsey Platten, Koya Ozawa, Reheman Adili, Nathalie Pamir, Forrest Nussdorfer, Alexander St John, Minhua Ling, Jennie Le, Jeff Harris, Nicole Rhoads, Yi Wang, Xiaoyun Fu, Junmei Chen, Sergio Fazio, Jonathan R Lindner, José A López
• Journal: Blood (Blood) Vol. 142 Issue 13 Pg. 1156-1166 (09 28 2023) ISSN: 1528-0020 [Electronic] United States
• PMID: 37506337 (Publication Type: Journal Article)
• Copyright: © 2023 by The American Society of Hematology.

Chemical References

• von Willebrand Factor
• Lipoproteins, LDL
• ADAMTS13 Protein

Topics

• Mice
• Humans
• Animals
• von Willebrand Factor (metabolism)
• Lipoproteins, LDL
• Thrombosis (metabolism)
• Hemostasis
• Platelet Adhesiveness
• ADAMTS13 Protein