ADAMTS13 gene deletion aggravates ischemic brain damage: a possible neuroprotective role of ADAMTS13 by ameliorating postischemic hypoperfusion

Abstract

Reperfusion after brain ischemia causes thrombus formation and microcirculatory disturbances, which are dependent on the platelet glycoprotein Ib-von Willebrand factor (VWF) axis. Because ADAMTS13 cleaves VWF and limits platelet-dependent thrombus growth, ADAMTS13 may ameliorate ischemic brain damage in acute stroke. We investigated the effects of ADAMTS13 on ischemia-reperfusion injury using a 30-minute middle cerebral artery occlusion model in Adamts13 ؊/؊ and wild-type mice. After reperfusion for 0.5 hours, the regional cerebral blood flow in the ischemic cortex was decreased markedly in Adamts13 ؊/؊ mice compared with wild-type mice (P < .05), which also resulted in a larger infarct volume after 24 hours for Adamts13 ؊/؊ compared with wild-type mice (P < .01). Thus, Adamts13 gene deletion aggravated ischemic brain damage, suggesting that ADAMTS13 may protect the brain from ischemia by regulating VWF-platelet interactions after reperfusion. These results indicate that ADAMTS13 may be a useful therapeutic agent for stroke. (Blood. 2010; 115:1650-1653) Introductionvon Willebrand factor (VWF) is a large multimeric protein that plays a key role in thrombus formation by tethering platelets at sites of vascular injury. 1 Smaller VWF multimers are less active, and the potent thrombogenic activity of ultra-large VWF (ULVWF) secreted from endothelium is regulated in vivo through cleavage by ADAMTS13. 2,3 The importance of this mechanism for normal hemostasis is supported by evidence that patients with deficiency of ADAMTS13 function, diagnosed with thrombotic thrombocytopenic purpura, have ULVWF in circulating blood and VWFdependent microvascular thrombosis. 2 Recently, we demonstrated that ADAMTS13 cleaves VWF on the surface of platelet thrombi in a shear force-dependent manner, which limits thrombus growth in vitro. 4 These data suggest that ADAMTS13 is a key molecule that maintains a physiologic balance between hemostasis and thrombosis through regulation of VWF function in vivo.ADAMTS13 function is crucial for preventing thrombosis in the cerebral microvasculature, as indicated by the occurrence of neurologic deficits in thrombotic thrombocytopenic purpura, but the role of ADMTS13 in the pathogenesis of reperfusion injury after arterial thrombosis has not been established. To address this issue, we investigated the role of ADAMTS13 in a transient middle cerebral arterial occlusion (MCAO) model of ischemia-reperfusion injury in the mouse brain 5 using Adamts Ϫ/Ϫ mice. 6 Because brain ischemia-reperfusion injury is dependent on the platelet glycoprotein Ib-VWF axis 7 and platelet thrombosis adversely affects the postischemic cerebral microcirculation 8-11 leading to secondary brain damage, 10 ADAMTS13 may reduce platelet thrombus growth and thereby ameliorate ischemic brain injury by improving the postischemic no-reflow phenomenon. 12 Here we demonstrate that Adamts13 gene deletion aggravates postischemic cerebral blood reflow, resulting in larger infarct volume. This result suggests that ADAMTS13 may indeed supp...

Platelet-delivered ADAMTS13 inhibits arterial thrombosis and prevents thrombotic thrombocytopenic purpura in murine models

“…Each has been shown to benefit from intravenous infusion of rADAMTS13. 46,47 The rADAMTS13 delivered by platelets may have greater advantages than that delivered by plasma because ;99.5% of therapeutic rADAMTS13 protein is stored inside platelets, which is available for release locally at high concentration on physiological stimulation. This strategy may potentially prolong the duration of rADAMTS13 action because of the longer half-life of platelets than soluble rADAMTS13 (3 days vs 20-30 minutes).…”

Relevant role of von Willebrand factor in neutrophil recruitment in a mouse sepsis model involving cecal ligation and puncture

“…Although the functional regulation of VWF has recently been proven beneficial in various diseases, [3][4][5][6]15 VWF-dependent inflammatory responses should be carefully considered in the context of these clinical applications.…”

“…Shogo Kasuda, 1 Hideto Matsui,2 Shiro Ono, 2 Yasunori Matsunari, 2 Kenji Nishio, 3 Midori Shima, 4 Katsuhiko Hatake, 1 …”

“…1,2 From the standpoint of the human defense system, VWF could, therefore, be a key protein serving as a functional link between inflammation and thrombosis. 2 Indeed, recent mouse model studies demonstrated that proper functional regulation of VWF-dependent inflammatory responses by ADAMTS13 considerably suppressed disease progression in patients with brain stroke 3,4 or myocardial infarction. 5,6 However, the precise mechanisms and roles of VWF in inflammation remain poorly understood thus far.…”

ADAMTS13, la protéase spécifique du clivage du facteur von Willebrand

“…Plus récemment, le rôle d'ADAMTS13 dans la thrombose artérielle a été évo-qué selon un concept qui souligne sa position de lien entre l'inflammation et la thrombose [49]. Au-delà du modèle « vertical » du PTT, cette dernière observation ouvre donc de nouveaux champs d'investigation pour la recherche dédiée à ADAMTS13, plus particulièrement ciblés sur les pathologies vasculaires [50]. [1,30].…”