@article{eea186d76ff14798ac6f474a97819d13,
title = "Reduced Proteolytic Cleavage of von Willebrand Factor Leads to Aortic Valve Stenosis and Load-Dependent Ventricular Remodeling",
abstract = "We hypothesized that excess endothelial-associated von Willebrand factor (vWF) and secondary platelet adhesion contribute to aortic valve stenosis (AS). We studied hyperlipidemic mice lacking ADAMTS13 (LDLR−/−AD13−/−), which cleaves endothelial-associated vWF multimers. On echocardiography and molecular imaging, LDLR−/−AD13−/− compared with control strains had increased aortic endothelial vWF and platelet adhesion and developed hemodynamically significant AS, arterial stiffening, high valvulo-aortic impedance, and secondary load-dependent reduction in LV systolic function. Histology revealed leaflet thickening and calcification with valve interstitial cell myofibroblastic and osteogenic transformation, and evidence for TGFβ1 pathway activation. We conclude that valve leaflet endothelial vWF-platelet interactions promote AS through juxtacrine platelet signaling.",
keywords = "aortic valve stenosis, echocardiography, von Willebrand factor",
author = "Koya Ozawa and Muller, {Matthew A.} and Oleg Varlamov and Hagen, {Matthew W.} and William Packwood and Morgan, {Terry K.} and Aris Xie and L{\'o}pez, {Claudia S.} and Dominic Chung and Junmei Chen and L{\'o}pez, {Jos{\'e} A.} and Lindner, {Jonathan R.}",
note = "Funding Information: Study protocols were supported by the Oregon Health & Sciences University Multiscale Microscopy Core and the Oregon National Primate Research Center Integrative Pathology Core. Dr Ozawa is supported by fellowship grants from the Japanese Society for the Promotion of Research, the Manpei Suzuki Diabetes Foundation, and the Japanese Society of Echocardiography. Dr L{\'o}pez is supported by grant R35-HL145262 from the National Institutes of Health. Dr Lindner is supported by grants R01-HL078610, R01-HL130046, and P51-OD011092 from the U.S. National Institutes of Health; and grant 18-18HCFBP_2-0009 from the U.S. National Aeronautics and Space Administration. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = jul,
doi = "10.1016/j.jacbts.2022.02.021",
language = "English (US)",
volume = "7",
pages = "642--655",
journal = "JACC: Basic to Translational Science",
issn = "2452-302X",
publisher = "Elsevier Inc.",
number = "7",
}