Recombinant ADAMTS13 reduces tissue plasminogen activator‐induced hemorrhage after stroke in mice

Wang, Lixiang; Fan, Wenying; Cai, Ping; Fan, Mengchen; Zhu, Ximin; Dai, Yiqin; Sun, Chungang; Cheng, Yannan; Zheng, Ping; Zhao, Bing-Qiao

doi:10.1002/ana.23762

Cited by 71 publications

(68 citation statements)

References 52 publications

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“…13,24 Treatment with rADAMTS13 effectively induced the expression of human ADAMTS13 at 14 days after stroke (supplemental Figure 6A). To examine the effects of a combined rADAMTS13 and VWF approach on neovascularization and BBB permeability, human VWF (5 mg/mouse; Haematologic Technologies, Essex Junction, VT) was administrated IV with rADAMTS13 into mice once per day for 1 week.…”

Section: Treatment Regimensmentioning

confidence: 96%

RETRACTED: ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

Cao

Yang

et al. 2017

Blood

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103

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Key Points• ADAMTS13 controls key steps of vascular remodeling during stroke recovery.• Recombinant ADAMTS13 enhances ischemic neovascularization and vascular repair.Angiogenic response is essential for ischemic brain repair. The von Willebrand factor (VWF)-cleaving protease disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) is required for endothelial tube formation in vitro, but there is currently no in vivo evidence supporting a function of ADAMTS13 in angiogenesis. Here we show that mice deficient in ADAMTS13 exhibited reduced neovascularization, brain capillary perfusion, pericyte and smooth muscle cell coverage on microvessels, expression of the tight junction and basement membrane proteins, and accelerated blood-brain barrier (BBB) breakdown and extravascular deposits of serum proteins in the peri-infarct cortex at 14 days after stroke. Deficiency of VWF or anti-VWF antibody treatment significantly increased microvessels, perfused capillary length, and reversed pericyte loss and BBB changes in Adamts13 2/2 mice. Furthermore, we observed that ADAMTS13 deficiency decreased angiopoietin-2 and galectin-3 levels in the isolated brain microvessels, whereas VWF deficiency had the opposite effect. Correlating with this, overexpression of angiopoietin-2 by adenoviruses treatment or administration of recombinant galectin-3 normalized microvascular reductions, pericyte loss, and BBB breakdown in Adamts13 2/2 mice. The vascular changes induced by angiopoietin-2 overexpression and recombinant galectin-3 treatment in Adamts13 2/2 mice were abolished by the vascular endothelial growth factor receptor-2 antagonist SU1498. Importantly, treating wild-type mice with recombinant ADAMTS13 at 7 days after stroke markedly increased neovascularization and vascular repair and improved functional recovery at 14 days. Our results suggest that ADAMTS13 controls key steps of ischemic vascular remodeling and that recombinant ADAMTS13 is a putative therapeutic avenue for promoting stroke recovery. (Blood. 2017;130(1):11-22)

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Section: Treatment Regimensmentioning

confidence: 96%

RETRACTED: ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

Cao

Yang

et al. 2017

Blood

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103

100

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“…16,22,23 However, the involvement of RAGE and its association with these pathogenic events remain unclear. The evidence shown here implicates the RAGE singling pathway in the development of EBI after ICH, thus presenting a possible therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

“…The BBB disruption and white matter fiber damage from EBI lead to early brain edema and sensorimotor dysfunction [23][24][25] and ultimately result in high morbidity and mortality.…”

Section: Discussionmentioning

confidence: 99%

Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage

Yang

Wang

Zhang³

et al. 2015

Stroke

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Background and Purpose-To determine whether the receptor for advanced glycation end-products (RAGE) plays a role in early brain injury from intracerebral hemorrhage (ICH), RAGE expression and activation after injury were examined in a rat model of ICH with or without administration of a RAGE-specific antagonist (FPS-ZM1). Methods-Autologous arterial blood was injected into the basal ganglia of rats to induce ICH. The motor function of the rats was examined, and water content was detected after euthanization. Blood-brain barrier permeability was determined by Evans blue staining and colloidal gold nanoparticle tracers. Nerve fiber injury in white matter was determined by diffusion tensor imaging analysis, and the expression of target genes was analyzed by Western blotting and quantitative reverse transcription polymerase chain reaction. FPS-ZM1 was administered by intraperitoneal injection. Results-Expression of RAGE and its ligand high-mobility group protein B1 were increased at 12 hours after ICH, along with blood-brain barrier permeability and perihematomal nerve fiber injury. RAGE and nuclear factor-κB p65 upregulation were also observed when FeCl 2 was infused into the basal ganglia at 24 hours. FPS-ZM1 administration resulted in significant improvements of blood-brain barrier damage, brain edema, motor dysfunction, and nerve fiber injury, and the expression of RAGE, nuclear factor-κB p65, proinflammatory mediators interleukin 1β, interleukin-6, interleukin-8R, cyclooxygenase-2, inducible nitric oxide synthase, and matrix metallopeptidase-9 was attenuated. Moreover, decreases in claudin-5 and occludin expression were partially recovered. FPS-ZM1 also reversed FeCl 2 -induced RAGE and nuclear factor-κB p65 upregulation. Conclusions-RAGE signaling is involved in blood-brain barrier and white matter fiber damage after ICH, the initiation of which is associated with iron. RAGE antagonists represent a novel therapeutic intervention to prevent early brain injury after ICH. .).The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Pickens

Mao

et al. 2015

Blood

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Recombinant ADAMTS13 reduces tissue plasminogen activator‐induced hemorrhage after stroke in mice

Abstract: These findings demonstrate that the VWF-cleaving protease rADAMTS13 reduced tPA-induced hemorrhage by regulating BBB integrity, and suggest that this effect may occur through the Akt/RhoA-mediated VEGF pathways.

Cited by 71 publications

References 52 publications

RETRACTED: ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

RETRACTED: ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage

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

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