Brain-Derived Extracellular Vesicles Induce Vasoconstriction and Reduce Cerebral Blood Flow in Mice

Wang, Jiwei; Xie, Xiaofeng; Wu, Yingang; Zhou, Yuan; Li, Qifeng; Liu, Ying; Xu, Xin; Wang, Min; Murdiyarso, Lydia; Houck, Katie; Hilton, Tristan; Chung, Dominic W.; Li, Min; Zhang, Jianning; Dong, Jing‐fei

doi:10.1089/neu.2021.0274

Cited by 12 publications

(16 citation statements)

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“…BDEV signi cantly increased in biological uids after TBI and may play an important role in the pathological development and prognosis after TBI [28,29]. BDEV can aggravate BBB damage, neuroin ammation and cerebral vasospasm [7,8,30]. Firstly, we prepared BDEV from the enzymatically dissociated brains 3h after TBI because a previous study found that circulating BDEV peaked at this time [6].…”

Section: Discussionmentioning

confidence: 99%

“…Brain induced extracellular vesicle (BDEV) released by damaged brain after TBI are recognized as the important pathobiological features of secondary brain damage [4]. Excessive production of BDEV is associated with coagulopathy, neuroin ammation and cerebral vasospasm [5][6][7]. A previous study showed that lactadherin improved BDEV-induced coagulopathy and prognosis in TBI mice by promoting the clearance of BDEV [8].…”

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confidence: 99%

“…However, an early clinical study found that nimodipine, an Ltype calcium channel blocker, showed no bene t in TBI patients, adding confusion to the mechanisms of neuronal damage caused by calcium in ux [19]. Recent studies showed that BDEV opened calcium channels of smooth muscle cells, which has sparked our interest in exploring the role of BDEV in brain injury [7].…”

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confidence: 99%

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NS1619 Alleviated Brain Derived Extracellular Vesicles Induced Brain Injury by Regulating the BKCa channel and Nrf2/Ho-1/Nf-kB Pathway

Gao

Zhang

et al. 2022

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Background Brain induced extracellular vesicle (BDEV) are increased after traumatic brain injury (TBI) but their role in secondary brain injury is unclear. The question whether and how BDEV is involved in secondary brain injury whether neuroprotective drugs BKCa channel openers NS1619 may attenuate BDEV-induced brain injury makes sense. Methods First, BDEV was extracted from enzymatically digested brains after TBI. Second, we injected BDEV and lactadherin to mimic the up- and down-regulation of BDEV respectively after TBI and determined the role of BDEV in vivo. In vitro, the membrane potential and calcium concentration of HT-22, bEnd3 and BV-2 were determined by DiBAC4 (3) staining and fluo4-AM staining respectively. The effects of BDEV and NS1619 on HT-22 were evaluated by CCK-8, LDH release assay, Na+/k+-ATPase activity, JC-1 staining, DHE staining, and 4-HNE staining respectively. The role of BDEV and NS1619 on the Nrf2/HO-1/p65 pathway was also evaluated in HT-22. Finally, we administration TBI mice with NS1619 to clarify the role of NS1619 against BDEV in vivo. Results BDEV injection aggravated and lactadherin mitigated TBI-induced EB leakage, brain edema, neuronal degeneration, apoptosis, ROS level, microgliosis, MMP-9 activity, and NF-kB activation. In vitro, BDEV-caused depolarized membrane potential and calcium overload were significantly attenuated by NS1619 in HT-22, bEnd3 and BV-2. BDEV markedly decreased cell viability, Na+/k+-ATPase activity and mitochondrial dysregulation, ROS, oxidative stress, NF-kB activation. NS1619 pretreatment alleviated above process and enhanced antioxidant system Nrf2/HO-1 in HT-22. NS1619 administration significantly improved TBI outcome. NS1619 facilitated microglial/macrophage phenotypic transformation and increased anti-inflammatory factor and decreased pro-inflammatory factors after TBI. Finally, NS1619 treatment reduced 4-HNE and NF-kB activation and enhanced Nrf2/HO-1 pathway. Conclusions BDEV aggravated brain injury after TBI by perturbing cell membrane potential, calcium homeostasis, oxidative stress and neuroinflammation. The BKCa channel opener NS1619 attenuated BDEV-induced pathological process in vitro and in vivo by modulating the BKCa channel and Nrf1/HO-1/p65 pathway.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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NS1619 Alleviated Brain Derived Extracellular Vesicles Induced Brain Injury by Regulating the BKCa channel and Nrf2/Ho-1/Nf-kB Pathway

Gao

Zhang

et al. 2022

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“…Microparticles (MPs, also called microvesicles) with multiple biological effects may link these pathological changes in tandem and there is the latest evidence supporting the direct involvement of MPs in CVS ( Wang et al, 2022 ). Their results demonstrate that brain-derived microparticles (BDMPs) constrict blood vessels depending on their structure.…”

Section: Introductionmentioning

confidence: 99%

“…The latest research found that BDMPs injection decreased cerebral blood flow, which is proven to cross the vascular endothelium and contract smooth muscle cells strongly. Furthermore, they could constrict isolated arteries and increase smooth muscle cytoplasmic calcium, which is partially blocked by nimodipine ( Wang et al, 2022 ). This study is the most direct evidence that MPs constrict smooth muscle cells and is very convincing.…”

Section: Introductionmentioning

confidence: 99%

Exploration of cerebral vasospasm from the perspective of microparticles

Gao

et al. 2022

Front. Neurosci.

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Cerebral vasospasm is a frequently encountered clinical problem, especially in patients with traumatic brain injury and subarachnoid hemorrhage. Continued cerebral vasospasm can cause cerebral ischemia, even infarction and delayed ischemic neurologic deficits. It significantly affects the course of the disease and the outcome of the patient. However, the underlying mechanism of cerebral vasospasm is still unclear. Recently, increasing studies focus on the pathogenic mechanism of microparticles. It has been found that microparticles have a non-negligible role in promoting vasospasm. This research aims to summarize the dynamics of microparticles in vivo and identify a causal role of microparticles in the occurrence and development of cerebral vasospasm. We found that these various microparticles showed dynamic characteristics in body fluids and directly or indirectly affect the cerebral vasospasm or prompt it. Due to the different materials carried by microparticles from different cells, there are also differences in the mechanisms that lead to abnormal vasomotor. We suggest that microparticle scavengers might be a promising therapeutic target against microparticles associated complications.

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Brain-derived extracellular vesicles mediate traumatic brain injury associated multi-organ damage

Liu

et al. 2023

Biochemical and Biophysical Research Communications

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Brain-Derived Extracellular Vesicles Induce Vasoconstriction and Reduce Cerebral Blood Flow in Mice

Cited by 12 publications

References 52 publications

NS1619 Alleviated Brain Derived Extracellular Vesicles Induced Brain Injury by Regulating the BKCa channel and Nrf2/Ho-1/Nf-kB Pathway

NS1619 Alleviated Brain Derived Extracellular Vesicles Induced Brain Injury by Regulating the BKCa channel and Nrf2/Ho-1/Nf-kB Pathway

Exploration of cerebral vasospasm from the perspective of microparticles

Brain-derived extracellular vesicles mediate traumatic brain injury associated multi-organ damage

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