Proteolysis of Von Willebrand Factor Influences Inflammatory Endothelial Activation and Vascular Compliance in Atherosclerosis

Abstract

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Reduced Proteolytic Cleavage of von Willebrand Factor Leads to Aortic Valve Stenosis and Load-Dependent Ventricular Remodeling

“…In animal models of hyperlipidemia, vWF-mediated platelet adhesion is known to accelerate atherosclerosis and to promote the recruitment of cells of the innate immune system to areas of plaque formation. 6 , 8 , 9 Accordingly, the increase in aortic root plaque formation seen in LDLR −/− AD13 −/− mice was not unexpected and, in many cases, there appeared to be an extension of plaque onto the valve leaflet surface. Yet, most of the valve thickening in LDLR −/− AD13 −/− mice was attributable not to inflammatory plaque formation, but rather to extensive proliferation of VICs with evidence for myofibroblastic and osteogenic transformation, an expansion of collagen-rich matrix, MMP-9 up-regulation, and microcalcification.…”

“…We evaluated hyperlipidemic mice deficient for LDLR fed a WSD that not only develop atherosclerosis but also have increased endothelial-associated vWF and adhesion of platelets to the arterial wall. 8 , 12 The additional genetic deletion of ADAMTS13 in these mice has been shown to markedly increase vWF-mediated platelet adhesion in the aorta and the development of large vessel atherosclerosis. 8 , 9 In the current study, LDLR −/− AD13 −/− mice on WSD demonstrated extensive vWF not only in atherosclerotic lesions, but also on VECs.…”

“… 8 , 12 The additional genetic deletion of ADAMTS13 in these mice has been shown to markedly increase vWF-mediated platelet adhesion in the aorta and the development of large vessel atherosclerosis. 8 , 9 In the current study, LDLR −/− AD13 −/− mice on WSD demonstrated extensive vWF not only in atherosclerotic lesions, but also on VECs. Most of these mice developed severe thickening of the aortic leaflets with increased transvalvular gradients in the traditionally stenotic range, representing a true model of AS, despite being studied at less than one-half the average lifespan of the background strain.…”

“… 4 , 5 , 6 , 7 These processes have been recognized to be proatherogenic. 8 , 9 Shear-mediated self-association of vWF and exposure of the A1 binding domain for platelet GPIbα could similarly contribute to AS through platelet binding and juxtacrine or paracrine signaling through factors such as transforming growth factor-β1 (TGFβ1) that are known to cause myofibroblastic or osteogenic activation of valvular cells. 10 , 11 Platelet adhesion to the surface of aortic leaflets has been described in mice with hyperlipidemia and on explanted leaflets from humans with AS.…”

Inflammatory Mediators of Platelet Activation: Focus on Atherosclerosis and COVID-19

“…The role of vWF and ADAMTS13 in atherosclerosis has also been recently proven in low-density lipoprotein receptor-deficient mice crossed with mice deficient for ADAMTS13, who were then treated with recombinant ADAMTS13. Following its administration, a reduction in endothelial vWF and platelet adhesion was noted, leading to a significant decrease in aortic plaque size [38].…”