cGMP-dependent protein kinase I in vascular smooth muscle cells improves ischemic stroke outcome in mice

Shvedova, Maria; Litvak, Maxim; Roberts, Jesse D.; Suzuki, Tomoaki; Şencan, İkbal; Li, Ge; Reventún, Paula; Buys, Emmanuel; Kim, Hyung-Hwan; Sakadžić, Sava; Ayata, Cenk; Huang, Paul L.; Feil, Robert; Atochin, Dmitriy N.

doi:10.1177/0271678x19870583

Cited by 11 publications

(9 citation statements)

References 92 publications

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“…7a-c). This phenomenon is consistent with the determination of cGMP in the affected side of the brain, which is an important mediator of NO-mediated vasodilation [34,47]. The cGMP levels in the TBI+IFX group were increased at 72 h compared to the TBI group but remained lower than the control group (Fig.…”

Section: Pericyte Degeneration Mediates Limited Perfusion Into the Ce...supporting

confidence: 88%

“…In our study, we found that inhibition of the TNF-α/NF-κB/iNOS axis by IFX could signi cantly ameliorate pericyte and TJ protein loss, thus contributing to the preservation of the integrity of BBB structure and function. We also measured the content of cGMP in brain tissue at 72 h postinjury, which is a mediator of NO-mediated vasodilation [34,47]. cGMP-related signaling is one of the pivotal mechanisms by which pericytes regulate blood ow [55,56].…”

Section: Discussionmentioning

confidence: 99%

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TNF-α Impairs Pericyte-Mediated Cerebral Microcirculation via the NF-κB/iNOS Axis after Experimental Traumatic Brain Injury

Zheng

Wang

Lin

et al. 2023

Journal of Neurotrauma

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BackgroundSecondary structural and functional abnormalities of the neurovascular unit are important pathological mechanisms following traumatic brain injury (TBI). The tumor necrosis factor α (TNF-α)/nuclear factor-κB (NF-κB) pathway regulates neuroin ammation and oxidative damage, which may act as triggers for pathological processes after TBI. However, the role of TNF-α/NF-κB in pericyte-mediated cerebral microcirculation are currently unknown. MethodsWe assessed the activity and mechanisms of the TNF-α/NF-κB signaling axis on pericyte-mediated microcirculation using the mouse controlled cortical impact model and BV2 cells. Immuno uorescent staining and western blot analysis were used to detect activation of the TNF-α/NF-κB signaling pathway and the expression of inducible nitric oxide synthase (iNOS) to evaluate the effects of the TNF-α speci c inhibitor in iximab (IFX). Modi ed neurological severity scores, Garcia test, Nissl staining, and TUNEL staining were employed to determine the neuroprotective effects of IFX supplementation. The relative blood ow values in the capillary areas surrounding the impinging lesion were observed by Laser speckle contrast imaging. The impact of IFX on pericyte markers was assessed to evaluate whether pericyte damage was dependent on the TNF-α/NF-κB/iNOS axis to gain further insight into the mechanisms underlying the development of the microcirculation disturbance after TBI. ResultsMicroglia were activated after TBI, and the expression of NF-κB, iNOS, a disintegrin and metalloproteinase 17, in ammatory factors, and free radicals increased around the injury areas. After lipopolysaccharide treatment, the expression of TNF-α and downstream NF-κB/iNOS in BV2 cells was signi cantly upregulated. Pharmacological inhibition of TNF-α via IFX signi cantly reduced NF-κB p65 phosphorylation and nuclear translocation and downregulated iNOS expression. Meanwhile, we found that speci c inhibition of TNF-α reversed pericyte marker loss, and improved pericyte function and cerebral microcirculation perfusion after TBI, which could attenuate in ammation and oxidative damage, reduce neuronal cell damage and apoptosis, and play a neuroprotective role. ConclusionThe results of this study suggested that microglia activated and released TNF-α after TBI, which promoted neuroin ammation and oxidative stress by activating downstream NF-κB/iNOS signals, and

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Section: Pericyte Degeneration Mediates Limited Perfusion Into the Ce...supporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

TNF-α Impairs Pericyte-Mediated Cerebral Microcirculation via the NF-κB/iNOS Axis after Experimental Traumatic Brain Injury

Zheng

Wang

Lin

et al. 2023

Journal of Neurotrauma

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“…Transient middle cerebral artery occlusion (tMCAO). WT CD-1 mice (male, 8-10 weeks old) were subjected to transient MCAO for 60 min and reperfusion for 48 h according to a previous report with some modification 85 . Briefly, mice were anesthetized with 1.5% isoflurane in oxygen.…”

Section: Measurement Of Oxygen Dissociation Curve (Odc)mentioning

confidence: 99%

Sulfide catabolism ameliorates hypoxic brain injury

et al. 2021

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The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain’s sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.

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“…32,34 Proper myogenic responses of SMCs are important for CBF regulation and steady capillary perfusion, protecting the brain against potentially negative effects of any rapid blood pressure change. 35 In addition, myogenic responses of SMCs are coupled to neuronal activity as nearby neurons and astrocytes release prostaglandins, nitric oxide, K þ and Ca 2þ to SMCs, 28,36 which precisely regulates brain tissue blood perfusion through SMC contraction or dilation. 37 In chronic hypertension and aging, SMCs undergo degeneration and the autoregulatory responses is often impaired, causing vascular injury, microbleeds and increased blood-brain barrier (BBB) permeability.…”

Section: Dysfunction Of the Neurovascular Unit Leads To Impaired Cbf ...mentioning

confidence: 99%

Recent advances in arterial spin labeling perfusion MRI in patients with vascular cognitive impairment

Huang

Guo

Guan

et al. 2022

J Cereb Blood Flow Metab

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Cognitive impairment (CI) is a major health concern in aging populations. It impairs patients’ independent life and may progress to dementia. Vascular cognitive impairment (VCI) encompasses all cerebrovascular pathologies that contribute to cognitive impairment (CI). Moreover, the majority of CI subtypes involve various aspects of vascular dysfunction. Recent research highlights the critical role of reduced cerebral blood flow (CBF) in the progress of VCI, and the detection of altered CBF may help to detect or even predict the onset of VCI. Arterial spin labeling (ASL) is a non-invasive, non-ionizing perfusion MRI technique for assessing CBF qualitatively and quantitatively. Recent methodological advances enabling improved signal-to-noise ratio (SNR) and data acquisition have led to an increase in the use of ASL to assess CBF in VCI patients. Combined with other imaging modalities and biomarkers, ASL has great potential for identifying early VCI and guiding prediction and prevention strategies. This review focuses on recent advances in ASL-based perfusion MRI for identifying patients at high risk of VCI.

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cGMP-dependent protein kinase I in vascular smooth muscle cells improves ischemic stroke outcome in mice

Cited by 11 publications

References 92 publications

TNF-α Impairs Pericyte-Mediated Cerebral Microcirculation via the NF-κB/iNOS Axis after Experimental Traumatic Brain Injury

TNF-α Impairs Pericyte-Mediated Cerebral Microcirculation via the NF-κB/iNOS Axis after Experimental Traumatic Brain Injury

Sulfide catabolism ameliorates hypoxic brain injury

Recent advances in arterial spin labeling perfusion MRI in patients with vascular cognitive impairment

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