scholarly journals Angiogenesis and Blood-Brain Barrier Permeability in Vascular Remodeling after Stroke

2020 ◽  
Vol 18 (12) ◽  
pp. 1250-1265 ◽  
Author(s):  
Yi Yang ◽  
Michel T. Torbey
Keyword(s):  
Tight Junction ◽  
Blood Brain Barrier ◽  
Defense Mechanism ◽  
Vascular Endothelial Cells ◽  
Brain Plasticity ◽  
Normal Function ◽  
Brain Barrier ◽  
Neurologic Recovery ◽  
Blood Brain ◽  
Bbb Permeability

Angiogenesis, the growth of new blood vessels, is a natural defense mechanism helping to restore oxygen and nutrient supply to the affected brain tissue following an ischemic stroke. By stimulating vessel growth, angiogenesis may stabilize brain perfusion, thereby promoting neuronal survival, brain plasticity, and neurologic recovery. However, therapeutic angiogenesis after stroke faces challenges: new angiogenesis-induced vessels have a higher than normal permeability, and treatment to promote angiogenesis may exacerbate outcomes in stroke patients. The development of therapies requires elucidation of the precise cellular and molecular basis of the disease. Microenvironment homeostasis of the central nervous system is essential for its normal function and is maintained by the blood-brain barrier (BBB). Tight junction proteins (TJP) form the tight junction (TJ) between vascular endothelial cells (ECs) and play a key role in regulating the BBB permeability. We demonstrated that after stroke, new angiogenesis-induced vessels in peri-infarct areas have abnormally high BBB permeability due to a lack of major TJPs in ECs. Therefore, promoting TJ formation and BBB integrity in the new vessels coupled with speedy angiogenesis will provide a promising and safer treatment strategy for improving recovery from stroke. Pericyte is a central neurovascular unite component in vascular barriergenesis and are vital to BBB integrity. We found that pericytes also play a key role in stroke-induced angiogenesis and TJ formation in the newly formed vessels. Based on these findings, in this article, we focus on regulation aspects of the BBB functions and describe cellular and molecular special features of TJ formation with an emphasis on role of pericytes in BBB integrity during angiogenesis after stroke.

scholarly journals TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer's microenvironment

2019 ◽  
Author(s):  
Qianshuo Liu ◽  
Lu Zhu ◽  
Xiaobai Liu ◽  
Jian Zheng ◽  
Yunhui Liu ◽  
...  
Keyword(s):  
Tight Junction ◽  
Blood Brain Barrier ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Brain Barrier ◽  
Blood Brain ◽  
Bbb Permeability ◽  
Novel Target ◽  
Related Proteins

Abstract The blood-brain barrier (BBB) plays a pivotal role in maintenance and regulation of the neural microenvironment. The occurrence of BBB disruption is the pathological change of early Alzheimer’s disease (AD). RNA-binding proteins and long non-coding RNAs are involved in the regulation of BBB permeability. Our study was performed to demonstrate TRA2A/LINC00662/ELK4 axis in regulating BBB permeability in AD microenvironment. In Aβ1-42-incubated microvascular endothelial cells (ECs) of BBB model in vitro, TRA2A and LINC00662 were enriched. TRA2A increased the stability of LINC00662 by binding with it. The knockdown of either TRA2A or LINC00662 decreased the BBB permeability via upregulating the expressions of tight junction-related proteins. ELK4 was lower expressed in BBB model in vitro in AD microenvironment. LINC00662 mediated the degradation of ELK4 mRNA by SMD pathway. The downregulated ELK4 increased the permeability of BTB by increasing the tight junction-related proteins expressions. TRA2A/LINC00662/ELK4 axis plays a crucial role in the regulation of BBB permeability in AD microenvironment, which may provide a novel target for the therapy of AD.

The role of hypoxia-inducible factor-1α, aquaporin-4, and matrix metalloproteinase-9 in blood-brain barrier disruption and brain edema after traumatic brain injury

2011 ◽  
Vol 114 (1) ◽  
pp. 92-101 ◽  
Author(s):  
Tetsuhiro Higashida ◽  
Christian W. Kreipke ◽  
José A. Rafols ◽  
Changya Peng ◽  
Steven Schafer ◽  
...  
Keyword(s):  
Tight Junction ◽  
Brain Edema ◽  
Blood Brain Barrier ◽  
Hypoxia Inducible Factor ◽  
Brain Barrier ◽  
Tight Junction Proteins ◽  
Edema Formation ◽  
Blood Brain ◽  
Bbb Permeability ◽  
Junction Proteins

Object The present study investigated the role of hypoxia-inducible factor-1α (HIF-1α), aquaporin-4 (AQP-4), and matrix metalloproteinase-9 (MMP-9) in blood-brain barrier (BBB) permeability alterations and brain edema formation in a rodent traumatic brain injury (TBI) model. Methods The brains of adult male Sprague-Dawley rats (400–425 g) were injured using the Marmarou closed-head force impact model. Anti–AQP-4 antibody, minocycline (an inhibitor of MMP-9), or 2-methoxyestradiol (2ME2, an inhibitor of HIF-1α), was administered intravenously 30 minutes after injury. The rats were killed 24 hours after injury and their brains were examined for protein expression, BBB permeability, and brain edema. Expression of HIF-1α, AQP-4, and MMP-9 as well as expression of the vascular basal lamina protein (laminin) and tight junction proteins (zona occludens-1 and occludin) was determined by Western blotting. Blood-brain barrier disruption was assessed by FITC-dextran extravasation, and brain edema was measured by the brain water content. Results Significant (p < 0.05) edema and BBB extravasations were observed following TBI induction. Compared with sham-operated controls, the injured animals were found to have significantly (p < 0.05) enhanced expression of HIF-1α, AQP-4, and MMP-9, in addition to reduced amounts (p < 0.05) of laminin and tight junction proteins. Edema was significantly (p < 0.01) decreased after inhibition of AQP-4, MMP-9, or HIF-1α. While BBB permeability was significantly (p < 0.01) ameliorated after inhibition of either HIF-1α or MMP-9, it was not affected following inhibition of AQP-4. Inhibition of MMP reversed the loss of laminin (p < 0.01). Finally, while inhibition of HIF-1α significantly (p < 0.05) suppressed the expression of AQP-4 and MMP-9, such inhibition significantly (p < 0.05) increased the expression of laminin and tight junction proteins. Conclusions The data support the notion that HIF-1α plays a role in brain edema formation and BBB disruption via a molecular pathway cascade involving AQP-4 and MMP-9. Pharmacological blockade of this pathway in patients with TBI may provide a novel therapeutic strategy.

scholarly journals TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer's microenvironment

2019 ◽  
Author(s):  
Qianshuo Liu ◽  
Lu Zhu ◽  
Xiaobai Liu ◽  
Jian Zheng ◽  
Yunhui Liu ◽  
...  
Keyword(s):  
Tight Junction ◽  
Blood Brain Barrier ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Brain Barrier ◽  
Blood Brain ◽  
Bbb Permeability ◽  
Novel Target ◽  
Related Proteins

Abstract The blood-brain barrier (BBB) plays a pivotal role in maintenance and regulation of the neural microenvironment. The occurrence of BBB disruption is the pathological change of early Alzheimer’s disease (AD). RNA-binding proteins and long non-coding RNAs are involved in the regulation of BBB permeability. Our study was performed to demonstrate TRA2A/LINC00662/ELK4 axis in regulating BBB permeability in AD microenvironment. In Aβ1-42-incubated microvascular endothelial cells (ECs) of BBB model in vitro, TRA2A and LINC00662 were enriched. TRA2A increased the stability of LINC00662 by binding with it. The knockdown of either TRA2A or LINC00662 decreased the BBB permeability via upregulating the expressions of tight junction-related proteins. ELK4 was lower expressed in BBB model in vitro in AD microenvironment. LINC00662 mediated the degradation of ELK4 mRNA by SMD pathway. The downregulated ELK4 increased the permeability of BTB by increasing the tight junction-related proteins expressions. TRA2A/LINC00662/ELK4 axis plays a crucial role in the regulation of BBB permeability in AD microenvironment, which may provide a novel target for the therapy of AD.

scholarly journals RhoA/ROCK-2 Pathway Inhibition and Tight Junction Protein Upregulation by Catalpol Suppresses Lipopolysaccaride-Induced Disruption of Blood-Brain Barrier Permeability

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2371 ◽  
Author(s):  
Shan Feng ◽  
Li Zou ◽  
Hongjin Wang ◽  
Ran He ◽  
Ke Liu ◽  
...  
Keyword(s):  
Tight Junction ◽  
Signaling Pathway ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Tight Junction Protein ◽  
Brain Barrier ◽  
Endothelin 1 ◽  
Blood Brain ◽  
Junction Protein ◽  
Bbb Permeability

Lipopolysaccaride (LPS) directly or indirectly injures brain microvascular endothelial cells (BMECs) and damages the intercellular tight junction that gives rise to altered blood-brain barrier (BBB) permeability. Catalpol plays a protective role in LPS-induced injury, but whether catalpol protects against LPS-caused damage of BBB permeability and the underlying mechanism remain to be delineated. Prophylactic protection with catalpol (5 mg/kg, i.v.) consecutively for three days reversed the LPS-induced damage of BBB by decreased Evans Blue (EB) leakage and restored tight junctions in C57 mice. Besides, catalpol co-administrated with LPS increased BMECs survival, decreased their endothelin-1, TNF-Α and IL-6 secretion, improved transmembrane electrical resistance in a time-dependent manner, and in addition increased the fluorescein sodium permeability coefficient of BMECs. Also, transmission electron microscopy showed catalpol protective effects on tight junctions. Fluorescence staining displayed that catalpol reversed the rearrangement of the cytoskeleton protein F-actin and upregulated the tight junction protein of claudin-5 and ZO-1, which have been further demonstrated by the mRNA and protein expression levels of ZO-1, ZO-2, ZO-3, claudin-5, and occludin. Moreover, catalpol concurrently downregulated the mRNA and protein levels of RhoA, and ROCK2, the critical proteins in the RhoA/ROCK2 signaling pathway. This study thus indicated that catalpol, via inhibition of the RhoA/ROCK2 signaling pathway, reverses the disaggregation of cytoskeleton actin in BMECs and prevents down-regulation of junctional proteins, such as claudin-5, occludin, and ZO-1, and decreases endothelin-1 and inflammatory cytokine secretion, eventually alleviating the increase in LPS-induced BBB permeability.

scholarly journals Transforming Growth Factor-β Signaling Alters Substrate Permeability and Tight Junction Protein Expression at the Blood-Brain Barrier during Inflammatory Pain

2009 ◽  
Vol 29 (6) ◽  
pp. 1084-1098 ◽  
Author(s):  
Patrick T Ronaldson ◽  
Kristin M DeMarco ◽  
Lucy Sanchez-Covarrubias ◽  
Christine M Solinsky ◽  
Thomas P Davis
Keyword(s):  
Growth Factor ◽  
Protein Expression ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Inflammatory Pain ◽  
Transforming Growth Factor ◽  
Brain Barrier ◽  
Functional Integrity ◽  
Blood Brain ◽  
Bbb Permeability

Our laboratory has shown that peripheral inflammatory pain induced by λ-carrageenan (CIP) can increase blood-brain barrier (BBB) permeability and alter tight junction (TJ) protein expression leading to changes in BBB functional integrity. However, the intracellular signaling mechanisms involved in this pathophysiologic response have not been elucidated. Transforming growth factor (TGF)-β signaling pathways are known to regulate vascular integrity and permeability. Therefore, we examined the function of TGF-β signaling at the BBB in rats subjected to CIP. During CIP, serum TGF-β1 and protein expression of the TGF-β receptor activin receptor-like kinase-5 (ALK5) were reduced. Brain permeability to 14C-sucrose was increased and expression of TJ proteins (i.e., claudin-5, occludin, zonula occluden (ZO-1)) were also altered after 3 h CIP. Pharmacological inhibition of ALK5 with the selective inhibitor SB431542 further enhanced brain uptake of 14C-sucrose, increased TJ protein expression (i.e., claudin-3, claudin-5, occludin, ZO-1), and decreased nuclear expression of TGF-β/ALK5 signaling molecules (i.e., Smad2, Smad3), which suggests a role for TGF-β/ALK5 signaling in the regulation of BBB integrity. Interestingly, administration of exogenous TGF-β before CIP activated the TGF-β/ALK5 pathway and reduced BBB permeability to 14C-sucrose. Taken together, our data show that TGF-β/ALK5 signaling is, in part, involved in the regulation of BBB functional integrity.

scholarly journals Protein Nanoparticle Osmotic Pressure Modifies Nonselective Permeability of the Blood Brain Barrier by Increasing Membrane Fluidity

2020 ◽  
Author(s):  
Chen Li ◽  
LinLin Chen ◽  
YuanYuan Wang ◽  
TingTing Wang ◽  
Dong Di ◽  
...  
Keyword(s):  
Tight Junction ◽  
Osmotic Pressure ◽  
Membrane Fluidity ◽  
Blood Brain Barrier ◽  
Transmembrane Protein ◽  
Chloride Ions ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Blood Brain ◽  
Bbb Permeability

Abstract BackgroundIntracellular tension plays a crucial role in the destruction of the blood brain barrier (BBB) in response to lesion stimuli. Tight junction structure could be primarily affected by tension activity. In this study, we aimed to determine the effects of extracellular BBB damage on intracellular tension activity, and elucidate the mechanism underlying the effects of intracellular protein nanoparticle-dependent osmotic pressure on BBB permeability.MethodsThe intracellular tension for tight junction proteins occludin and ZO1 were evaluated using the fluorescence resonance energy transfer (FRET)-based tension probes and cpstFRET analysis. The efficiency of the probes was examined by acceptor photobleaching FRET (FRET-AB) analysis. The changes in mobility ratios of the transmembrane protein occludin were evaluated via the fluorescence recovery after photobleaching (FRAP) test. The cytoplasmic osmotic pressure (OP) was measured using the Osmomat 3000 Freezing Point Osmometer and 050 Membrane Osmometer. The count rate of cytoplasmic nanoparticles was detected by Nanosight NS300. The activation of cofilin and stathmin was examined by Western blot analysis. The BBB permeability in vivo was determined via investigating the changes of Evans Blue (EB) injected into the SD rats. The tight junction formation was assessed by the measurement of transendothelial electrical resistance (TEER). Intracellular calcium or chloride ions were measured using Fluo-4 AM or MQAE dyes. ResultsBBB lesions were accompanied by changes in occludin/ZO1 tension. Increases in intracellular osmotic pressure were involved in alteration of BBB permeability, possibly through the depolymerization of microfilaments or microtubules and mass production of protein nanoparticles according to the Donnan effect. Recovery of protein nanoparticle osmotic pressure could effectively reverse the effects of changes in occludin/ZO1 tension and BBB lesions. Outward tension of intracellular osmotic potential also caused upregulation of membrane fluidity, which promoted nonselective drug influx.ConclusionsOur results suggest a crucial mechanical mechanism underlying BBB lesions, and protein nanoparticle osmotic pressure could be a novel therapeutic target for BBB lesion-related brain diseases. Our results also provide a basis for further studies on the regulation of intracellular tension activity and its effect on the permeability of the BBB, and development of novel drugs that cross the blood-brain barrier.

scholarly journals TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer’s microenvironment

2019 ◽  
Author(s):  
Qianshuo Liu ◽  
Lu Zhu ◽  
Xiaobai Liu ◽  
Jian Zheng ◽  
Yunhui Liu ◽  
...  
Keyword(s):  
Tight Junction ◽  
Blood Brain Barrier ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Brain Barrier ◽  
Blood Brain ◽  
Bbb Permeability ◽  
Early Alzheimer’S Disease ◽  
Related Proteins

AbstractThe blood-brain barrier (BBB) has an important significance in maintenance and regulation of the neural microenvironment. The occurrence of BBB disruption is the pathological change of early Alzheimer’s disease (AD). RNA-binding proteins and long non-coding RNAs are closely related to the regulation of BBB permeability. Our study was performed to demonstrate TRA2A/LINC00662/ELK4 axis that regulates BBB permeability in AD microenvironment. In Aβ1-42-incubated microvascular endothelial cells (ECs) of BBB model in vitro, TRA2A and LINC00662 were enriched. TRA2A increased the stability of LINC00662 by binding with it. The knockdown of either TRA2A or LINC00662 decreased the BBB permeability via upregulating the levels of tight junction-related proteins. ELK4 was downregulated in BBB model in vitro in AD microenvironment. LINC00662 mediated the degradation of ELK4 mRNA by SMD pathway. The downregulated ELK4 increased the permeability of BTB by inducing the tight junction-related proteins. TRA2A/LINC00662/ELK4 axis is important in the regulation of BBB permeability in AD microenvironment, which would be a new molecular target for AD treatment.

scholarly journals Lipid polymeric nanoparticles modified with tight junction-modulating peptides promote afatinib delivery across a blood–brain barrier model

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yu-Li Lo ◽  
Hua-Ching Lin ◽  
Shu-Ting Hong ◽  
Chih-Hsien Chang ◽  
Chen-Shen Wang ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Polymeric Nanoparticles ◽  
Growth Factor Receptor ◽  
Brain Barrier ◽  
Polymeric Nanoparticle ◽  
Blood Brain ◽  
Blood Brain Barrier Model ◽  
Delivery Platform

Abstract Background Brain metastases from non-small cell lung cancer (NSCLC) remain one of the most challenging malignancies. Afatinib (Afa) is an orally administered irreversible ErbB family blocker approved for epidermal growth factor receptor (EGFR)-mutated NSCLC. However, the incidence of brain metastases in patients with NSCLC and EGFR mutation is high. One of the major obstacles in the treatment of brain metastases is to transport drugs across the blood–brain barrier (BBB). A lipid polymeric nanoparticle (LPN) modified with a tight junction-modulating peptide is a potential formulation to deliver therapeutics across the BBB. FD7 and CCD are short peptides that perturb the tight junctions (TJs) of the BBB. In this study, the use of LPN modified with FD7 or CCD as a delivery platform was explored to enhance Afa delivery across the BBB model of mouse brain-derived endothelial bEnd.3 cells. Results Our findings revealed that Afa/LPN-FD7 and Afa/LPN-CCD exhibited a homogeneous shape, a uniform nano-scaled particle size, and a sustained-release profile. FD7, CCD, Afa/LPN-FD7, and Afa/LPN-CCD did not cause a significant cytotoxic effect on bEnd.3 cells. Afa/LPN-FD7 and Afa/LPN-CCD across the bEnd.3 cells enhanced the cytotoxicity of Afa on human lung adenocarcinoma PC9 cells. FD7 and CCD-modulated TJ proteins, such as claudin 5 and ZO-1, reduced transendothelial electrical resistance, and increased the permeability of paracellular markers across the bEnd.3 cells. Afa/LPN-FD7 and Afa/LPN-CCD were also partially transported through clathrin- and caveolae-mediated transcytosis, revealing the effective activation of paracellular and transcellular pathways to facilitate Afa delivery across the BBB and cytotoxicity of Afa on PC9 cells. Conclusion TJ-modulating peptide-modified LPN could be a prospective platform for the delivery of chemotherapeutics across the BBB to the brain for the potential treatment of the BM of NSCLC.

scholarly journals Dual Roles of Astrocyte-Derived Factors in Regulation of Blood-Brain Barrier Function after Brain Damage

2019 ◽  
Vol 20 (3) ◽  
pp. 571 ◽  
Author(s):  
Shotaro Michinaga ◽  
Yutaka Koyama
Keyword(s):  
Brain Damage ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain ◽  
Secondary Damage ◽  
The Central Nervous System ◽  
Bbb Permeability ◽  
Novel Therapeutic Strategies ◽  
Glial Derived Neurotrophic Factor ◽  
Endothelial Growth Factors

The blood-brain barrier (BBB) is a major functional barrier in the central nervous system (CNS), and inhibits the extravasation of intravascular contents and transports various essential nutrients between the blood and the brain. After brain damage by traumatic brain injury, cerebral ischemia and several other CNS disorders, the functions of the BBB are disrupted, resulting in severe secondary damage including brain edema and inflammatory injury. Therefore, BBB protection and recovery are considered novel therapeutic strategies for reducing brain damage. Emerging evidence suggests key roles of astrocyte-derived factors in BBB disruption and recovery after brain damage. The astrocyte-derived vascular permeability factors include vascular endothelial growth factors, matrix metalloproteinases, nitric oxide, glutamate and endothelin-1, which enhance BBB permeability leading to BBB disruption. By contrast, the astrocyte-derived protective factors include angiopoietin-1, sonic hedgehog, glial-derived neurotrophic factor, retinoic acid and insulin-like growth factor-1 and apolipoprotein E which attenuate BBB permeability resulting in recovery of BBB function. In this review, the roles of these astrocyte-derived factors in BBB function are summarized, and their significance as therapeutic targets for BBB protection and recovery after brain damage are discussed.

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