Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening pulmonary vascular disease, characterized by persistent thrombotic obstruction and progressive pulmonary vascular remodeling, yet the molecular mechanisms linking persistent thrombosis to vascular remodeling remain incompletely understood. Clinical studies have reported elevated plasma von Willebrand factor (VWF) levels and reduced ADAMTS13 in patients with CTEPH, but whether VWF/ADAMTS13 dysregulation contributes directly to disease pathogenesis remains unclear. Here, using newly established rat models of CTEPH, we identify a causative role for dysregulation of the VWF/ADAMTS13 axis in chronic thromboembolic progression. CTEPH rats developed persistent, unresolved VWF- and fibrin-rich thrombi accompanied by markedly increased endothelial VWF deposition. In contrast, ADAMTS13 expression and activity were significantly reduced in CTEPH rats. Consistent with these findings, genetic Adamts13 deficiency further exacerbates pulmonary microvascular thrombosis and accelerated early mortality following disease induction. Mechanistically, ultra-large (UL)-VWF accumulated on the pulmonary endothelial surface, promoting robust platelet recruitment under shear. This platelet/VWF interaction stimulated the release of platelet-derived pro-remodeling mediators, including TGF-{beta}1 and PDGF-BB. Genetic ablation of Vwf markedly reduced in situ microvascular thrombosis within pulmonary arterioles, attenuated pulmonary arterial remodeling, and improved pulmonary hemodynamics. Moreover, treatment with recombinant ADAMTS13 reduced endothelial UL-VWF accumulation, suppressed platelet activation, and effectively prevented thrombosis and platelet-driven pro-remodeling signaling in CTEPH rats. Collectively, these findings identify dysregulation of the VWF/ADAMTS13 axis as a key driver of pulmonary thrombosis and vascular remodeling in CTEPH and support therapeutic targeting of this pathway as a potential disease-modifying strategy.
Wu, Z., Dong, H., Zhang, Q., Chai, Z., li, A., Dominguez, E. M., Zhao, X., Spikes, L., Soares, M., Long Zheng, X., Zheng, L.
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