Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage

Cai, Ping; Luo, Haiyu; Xu, Haochen; Zhu, Ximin; Xu, Wenjian; Dai, Yiqin; Jin, Xiao; Cao, Yongliang; Zhao, Yuwu; Zhao, Bing; Fan, Wenying

doi:10.1161/strokeaha.115.009526

Cited by 45 publications

(43 citation statements)

References 35 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%

“…10 In addition, ADAMTS13 was also shown to reduce both thrombosis and inflammation through the cleavage of VWF. [11][12][13] Angiogenesis is a complex process constituting multiple steps. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR-2) initiate angiogenesis, and angiopoietins (Angs) 1 and 2 are implicated in vascular maturation and stabilization.…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

confidence: 99%

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

Cao

Yang

et al. 2017

Blood

Self Cite

103

100

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“…To examine whether VWF deficiency affects BBB permeability and brain water content, the collagenase-induced ICH model was used47. In brief, mice were placed on a stereotactic frame and 0.5 μl of saline containing 0.025 U collagenase VII (Sigma-Aldrich) was injected into the left striatum at coordinates 0.2 mm anterior and 2.3 mm lateral to bregma, and 3.5 mm ventral to the skull surface.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) (Invitrogen, Camarillo, CA) supplemented with 10% fetal calf serum (Invitrogen) and antibiotics in a humidified cell culture incubator at 37 °C and 5% CO 2 47. Cells were incubated with VWF (10 ug/ml) for 24 hours47. Cytotoxicity was evaluated by a standard measurement of lactate dehydrogenase (LDH) release using the LDH assay kit (repeated three times in triplicate, Roche, Indianapolis, IN).…”

Section: Methodsmentioning

confidence: 99%

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von Willebrand factor contributes to poor outcome in a mouse model of intracerebral haemorrhage

Zhu

Cao

Wei

et al. 2016

Sci Rep

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Spontaneous intracerebral haemorrhage (ICH) is the most devastating stroke subtype and has no proven treatment. von Willebrand factor (VWF) has recently been demonstrated to promote inflammation processes. The present study investigated the pathophysiological role of VWF after experimental ICH. Functional outcomes, brain edema, blood-brain barrier (BBB) permeability, cerebral inflammation and levels of intercellular adhesion molecule-1 (ICAM-1) and matrix metalloproteinase-9 (MMP-9) were measured in a mouse model of ICH induced by autologous blood injection. We show that VWF were increased in the plasma and was accumulated in the perihematomal regions of mice subjected to ICH. Injection of VWF resulted in incerased expression of proinflammatory mediators and activation of ICAM-1 and MMP-9, associated with elevated myeloperoxidase, recruitment of neutrophils and microglia. Moreover, mice treated with VWF showed dramatically decreased pericyte coverage, more severe BBB damage and edema formation, and neuronal injury was increased compared with controls. In contrast, blocking antibodies against VWF reduced BBB damage and edema formation and improved neurological function. Together, these data identify a critical role for VWF in cerebral inflammation and BBB damage after ICH. The therapeutic interventions targeting VWF may be a novel strategy to reduce ICH-related injury.

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Astrocyte‐Derived Extracellular Vesicular miR‐143‐3p Dampens Autophagic Degradation of Endothelial Adhesion Molecules and Promotes Neutrophil Transendothelial Migration after Acute Brain Injury

Wu,

Liu,

et al. 2023

Advanced Science

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Pivotal roles of extracellular vesicles (EVs) in the pathogenesis of central nervous system (CNS) disorders including acute brain injury are increasingly acknowledged. Through the analysis of EVs packaged miRNAs in plasma samples from patients with intracerebral hemorrhage (ICH), it is discovered that the level of EVs packaged miR‐143‐3p (EVs‐miR‐143‐3p) correlates closely with perihematomal edema and neurological outcomes. Further study reveals that, upon ICH, EVs‐miR‐143‐3p is robustly secreted by astrocytes and can shuttle into brain microvascular endothelial cells (BMECs). Heightened levels of miR‐143‐3p in BMECs induce the up‐regulated expression of cell adhesion molecules (CAMs) that bind to circulating neutrophils and facilitate their transendothelial cell migration (TEM) into brain. Mechanism‐wise, miR‐143‐3p directly targets ATP6V1A, resulting in impaired lysosomal hydrolysis ability and reduced autophagic degradation of CAMs. Importantly, a VCAM‐1–targeting EVs system to selectively deliver miR‐143‐3p inhibitor to pathological BMECs is created, which shows satisfactory therapeutic effects in both ICH and traumatic brain injury (TBI) mouse models. In conclusion, the study highlights the causal role of EVs‐miR‐143‐3p in BMECs’ dysfunction in acute brain injury and demonstrates a proof of concept that engineered EVs can be devised as a potentially applicable nucleotide drug delivery system for the treatment of CNS disorders.

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Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage

Cited by 45 publications

References 35 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

von Willebrand factor contributes to poor outcome in a mouse model of intracerebral haemorrhage

Astrocyte‐Derived Extracellular Vesicular miR‐143‐3p Dampens Autophagic Degradation of Endothelial Adhesion Molecules and Promotes Neutrophil Transendothelial Migration after Acute Brain Injury

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