Mechanisms of modulation of brain microvascular endothelial cells function by thrombin

Brǎiloiu, Eugen; Shipsky, Megan M.; Yan, Guang; Abood, Mary E.; Brailoiu, G. Cristina

doi:10.1016/j.brainres.2016.12.011

Cited by 48 publications

(58 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, thrombin triggered platelet activation which could release inflammatory cytokines and disrupt the integrity of endothelial cell monolayers . Claudin‐5, ZO‐1, and other tight junction proteins also contributed to the thrombin‐induced increase in vascular permeability . But their roles in hydrocephalus still remain to be understood.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Thrombin disrupts vascular endothelial‐cadherin and leads to hydrocephalus via protease‐activated receptors‐1 pathway

Hao

Zhang

et al. 2019

CNS Neurosci Ther

View full text Add to dashboard Cite

Summary Aims Previous studies indicated that intraventricular injection of thrombin would induce hydrocephalus. But how thrombin works in this process remains unclear. Since cadherin plays a critical role in hydrocephalus, we aimed to explore the mechanisms of how thrombin acted on choroid plexus vascular endothelium and how thrombin interacted with vascular endothelial‐cadherin (VE‐cadherin) during hydrocephalus. Methods There were two parts in this study. Firstly, rats received an injection of saline or thrombin into the right lateral ventricle. Magnetic resonance imaging was applied to measure the lateral ventricle volumes. Albumin leakage and Evans blue content were assessed to test the blood‐brain barrier function. Immunofluorescence and Western blot were applied to detect the location and the expression of VE‐cadherin. Secondly, we observed the roles of protease‐activated receptors‐1 (PAR1) inhibitor (SCH79797), Src inhibitor (PP2), p21‐activated kinase‐1 (PAK1) inhibitor (IPA3) in the thrombin‐induced hydrocephalus, and their effects on the regulation of VE‐cadherin. Results Our study demonstrated that intraventricular injection of thrombin caused significant downregulation of VE‐cadherin in choroid plexus and dilation of ventricles. In addition, the inhibition of PAR1/p‐Src/p‐PAK1 pathway reversed the decrease of VE‐cadherin and attenuated thrombin‐induced hydrocephalus. Conclusions Our results suggested that the thrombin‐induced hydrocephalus was associated with the inhibition of VE‐cadherin via the PAR1/p‐Src/p‐PAK1 pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

“…43 Claudin-5, ZO-1, and other tight junction proteins also contributed to the thrombininduced increase in vascular permeability. 38,44,45 But their roles in hydrocephalus still remain to be understood. Future studies will examine more detailed scenarios of hydrocephalus after IVH.…”

Section: Discussionsmentioning

confidence: 99%

Thrombin disrupts vascular endothelial‐cadherin and leads to hydrocephalus via protease‐activated receptors‐1 pathway

Hao

Zhang

et al. 2019

CNS Neurosci Ther

View full text Add to dashboard Cite

show abstract

“…Most of the thrombin-mediated harmful action occurs through a protease-activated receptor (PER) 1, but additional receptors sites PER 2, 3, 4 (Bartha et al, 2000; Choi et al, 2008; Vajda et al, 2008) may be involved as well. Thrombin increases cytosolic Ca 2+ concentration via releasing Ca 2+ from endoplasmic reticulum through IP 3 activation (Brailoiu et al, 2017). It also increases nitric oxide (NO) production and reactive oxygen species in the mitochondria and cytosol.…”

Section: Recently Identified Therapeutic Aims and Therapiesmentioning

confidence: 99%

“…It also increases nitric oxide (NO) production and reactive oxygen species in the mitochondria and cytosol. Furthermore, it increases fibrin stress fibers in brain microvascular endothelial cells resulting in BBB leakage (Brailoiu et al, 2017). Direct acting thrombin antagonists such as Dabigatran have been shown to decrease the size of infarction, inflammation, and BBB permeability (Dittmeier et al, 2016).…”

Section: Recently Identified Therapeutic Aims and Therapiesmentioning

confidence: 99%

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

Shekhar

Cunningham

Pabbidi

et al. 2018

European Journal of Pharmacology

View full text Add to dashboard Cite

Ischemic stroke is a devastating and debilitating medical condition with limited therapeutic options. However, accumulating evidence indicates a central role of inflammation in all aspects of stroke including its initiation, the progression of injury, and recovery or wound healing. A central target of inflammation is disruption of the blood brain barrier or neurovascular unit. Here we discuss recent developments in identifying potential molecular targets and immunomodulatory approaches to preserve or protect barrier function and limit infarct damage and functional impairment. These include blocking harmful inflammatory signaling in endothelial cells, microglia/macrophages, or Th17/γδ T cells with biologics, third generation epoxyeicosatrienoic acid (EET) analogs with extended half-life, and miRNA antagomirs. Complementary beneficial pathways may be enhanced by miRNA mimetics or hyperbaric oxygenation. These immunomodulatory approaches could be used to greatly expand the therapeutic window for thrombolytic treatment with tissue plasminogen activator (t-PA). Moreover, nanoparticle technology allows for the selective targeting of endothelial cells for delivery of DNA/RNA oligonucleotides and neuroprotective drugs. In addition, although likely detrimental to the progression of ischemic stroke by inducing inflammation, oxidative stress, and neuronal cell death, 20-HETE may also reduce susceptibility of onset of ischemic stroke by maintaining autoregulation of cerebral blood flow. Although the interaction between inflammation and stroke is multifaceted, a better understanding of the mechanisms behind the pro-inflammatory state at all stages will hopefully help in developing novel immunomodulatory approaches to improve mortality and functional outcome of those inflicted with ischemic stroke.

show abstract

“…CMECs, which are one of the main components of neurovascular units, contribute to formation of the BBB, participate in the body’s metabolism and endocrine synthesis, and synthesize and release dozens of bioactive substances [19]. In addition, these cells play an important role in regulating and maintaining stability and balance of the neurovascular microenvironment in the brain.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen-Rich Saline Attenuates Brain Injury Induced by Cardiopulmonary Bypass and Inhibits Microvascular Endothelial Cell Apoptosis Via the PI3K/Akt/GSK3β Signaling Pathway in Rats

Chen¹,

Wang²,

Diao³

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Cardiopulmonary bypass (CPB) is prone to inducing brain injury during open heart surgery. A hydrogen-rich solution (HRS) can prevent oxidation and apoptosis, and inhibit inflammation. This study investigated effects of HRS on brain injury induced by CPB and regulatory mechanisms of the PI3K/Akt/GSK3β signaling pathway. Methods: A rat CPB model and an in vitro cell hypoxia model were established. After HRS treatment, Rat behavior was measured using neurological deficit score; Evans blue (EB) was used to assess permeability of the blood-brain barrier (BBB); HE staining was used to observe pathological changes; Inflammatory factors and brain injury markers were detected by ELISA; the PI3K/Akt/GSK3β pathway-related proteins and apoptosis were assessed by western blot, immunohistochemistry and qRT –PCR analyses of brain tissue and neurons. Results: After CPB, brain tissue anatomy was disordered, and cell structure was abnormal. Brain tissue EB content increased. There was an increase in the number of apoptotic cells, an increase in expression of Bax and caspase-3, a decrease in expression of Bcl2, and increases in levels of Akt, GSK3β, P-Akt, and P-GSK3β in brain tissue. HRS treatment attenuated the inflammatory reaction ,brain tissue EB content was significantly reduced and significantly decreased expression levels of Bax, caspase-3, Akt, GSK3β, P-Akt, and P-GSK3β in the brain. After adding the PI3K signaling pathway inhibitor, LY294002, to rat cerebral microvascular endothelial cells (CMECs), HRS could reduce activated Akt expression and downstream regulatory gene phosphorylation of GSK3β expression, and inhibit CMEC apoptosis. Conclusion: The PI3K/Akt/GSK3β signaling pathway plays an important role in the mechanism of CPB-induced brain injury. HRS can reduce CPB-induced brain injury and inhibit CMEC apoptosis through the PI3K/Akt/GSK3β signaling pathway.

show abstract

Mechanisms of modulation of brain microvascular endothelial cells function by thrombin

Cited by 48 publications

References 58 publications

Thrombin disrupts vascular endothelial‐cadherin and leads to hydrocephalus via protease‐activated receptors‐1 pathway

Thrombin disrupts vascular endothelial‐cadherin and leads to hydrocephalus via protease‐activated receptors‐1 pathway

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

Hydrogen-Rich Saline Attenuates Brain Injury Induced by Cardiopulmonary Bypass and Inhibits Microvascular Endothelial Cell Apoptosis Via the PI3K/Akt/GSK3β Signaling Pathway in Rats

Contact Info

Product

Resources

About