bims-blobar Biomed News
on Blood brain barrier repair
Issue of 2025–09–21
thirteen papers selected by
Nicolas Rebergue
  1. Endothelial αvβ3 integrin induction during hypoxia protects blood-brain barrier integrity.
  2. Activation of the liver X receptor α protects the blood-brain barrier against heatstroke-induced injury.
  3. Telmisartan Ameliorates Blood-Brain Barrier Disruption in a High-Salt Diet Mouse Model.
  4. Endothelial GATAD1 Exacerbates Blood-brain Barrier Dysfunction in Ischemic Stroke through Caveolae-mediated Transcytosis.
  5. Stress-Induced Regional Characteristics of the Blood-Brain Barrier.
  6. Neutrophil extracellular traps induce endothelial damage and exacerbate vasospasm in traumatic brain injury.
  7. Blood-brain barrier-associated serum proteins in epilepsy - clinical and diagnostic implications.
  8. Astrocytic Cannabinoid Receptor 1 Governs Stress Resilience by Orchestrating Blood-Brain Barrier Integrity.
  9. Isolation and Imaging of Microvessels From Brain Tissue.
  10. Characterization of a Ferret Model of Traumatic Brain Injury due to Under-Vehicle Blast, Controlled Cortical Impact, or Blast Plus Impact.
  11. Intravenous lipid-siRNA conjugate mediates gene silencing at the blood-brain barrier and blood-CSF barrier.
  12. A physiological microfluidic blood-brain-barrier model for in vitro study of nanoparticle trafficking and accumulation.
  13. Early olfactory dysfunction in experimental autoimmune encephalomyelitis reflects transient brain barrier breach and initiation of neuroinflammation in the olfactory bulb.
  1. Proc Natl Acad Sci U S A. 2025 Sep 23. 122(38): e2510931122
    Endothelial αvβ3 integrin induction during hypoxia protects blood-brain barrier integrity.
    Sebok K Halder, Violaine D Delorme-Walker, Richard Milner.
      The blood-brain barrier (BBB) is critical for maintaining cerebral homeostasis, and its deterioration with age is an important pathogenic factor in the etiology of vascular dementia. Extracellular matrix-integrin interactions play a central role in regulating vascular stability. The αvβ3 integrin is not expressed by brain endothelial cells under stable conditions but is strongly induced by hypoxia. However, it is currently unclear whether αvβ3 integrin exerts a destructive or protective influence on BBB integrity. In young (8 to 10 wk) and aged (20 mo) mice, we examined the impact of a function-blocking β3 integrin antibody as well as the inhibitory peptide cilengitide on BBB disruption during exposure to CMH (8% O2). Hypoxic induction of brain endothelial β3 integrin was much stronger in aged mice. In both young and aged mice, β3 integrin inhibition greatly amplified hypoxia-induced BBB disruption, correlating with loss of tight junction proteins and induction of the leaky BBB marker mouse endothelial cell antigen (MECA)-32. Consistent with this, β3 integrin null mice showed increased levels of hypoxia-induced BBB disruption and MECA-32 expression. Cilengitide also reduced the integrity of a brain endothelial monolayer in vitro, prevented β3 integrin localization to focal adhesions, and reduced expression of vascular endothelial (VE)-cadherin and tight junction proteins. These observations suggest that hypoxic induction of endothelial αvβ3 integrin enhances BBB integrity by stabilizing endothelial adhesion. This raises the interesting possibility that pharmacological upregulation of endothelial αvβ3 integrin in the aged brain might hold therapeutic promise for vascular dementia.
    Keywords:  aging; blood vessels; brain; chronic mild hypoxia; β3 integrin
    DOI:  https://doi.org/10.1073/pnas.2510931122
  2. Int J Hyperthermia. 2025 Dec;42(1): 2559022
    Activation of the liver X receptor α protects the blood-brain barrier against heatstroke-induced injury.
    Ping Li, Xiaoqian Liu, Xue Luo, Zhen Luo, Genlin He, Xuesen Yang.
       BACKGROUND: Impairment of blood-brain barrier (BBB) contributes significantly to neuroinflammation and central nervous system (CNS) dysfunction in heatstroke. Our previous study revealed activation of liver X receptor α (LXRα) alleviates the heat stress-induced proinflammatory response in CNS; however, whether this protective effect is mediated by maintaining BBB integrity remains unknown. In this study, we focused on BBB integrity to explore the underlying mechanisms of LXRα in heatstroke.
    METHODS: T0901317 (T0), an agonist of LXRα, was used to activate LXRα both in vivo and in vitro. Neurological deficits, neuroinflammation and BBB disruption were measured after mice were subjected to heatstroke. The BBB-mediated protective mechanism of LXRα activation in heatstroke was explored with brain microvascular endothelial cells in vitro.
    RESULTS: Administration of T0 immediately after the onset of heatstroke significantly ameliorated heatstroke-induced neuroinflammation and neurological deficits. In addition, BBB leakage caused by heatstroke was alleviated by T0, and this protective effect was achieved by enhancing tight junctions in brain microvascular endothelial cells. Mechanistically, we found that expression of ATP-binding cassette transporter A1 (ABCA1) was increased after LXRα activation, whereas ABCA1 knockdown using esiRNAs abolished LXRα activation-mediated BBB preservation by suppressing the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) signaling pathway in brain microvascular endothelial cells.
    CONCLUSIONS: Our results indicated that LXRα activation could alleviate neuroinflammation and CNS dysfunction in heatstroke by maintaining BBB integrity, and relevant mechanisms may be related to JAK2/STAT3 signal activation via ABCA1. This research provide a novel strategy for managing heatstroke-associated BBB dysfunction.
    Keywords:  Blood–brain barrier; brain microvascular endothelial cell; heatstroke; liver X receptor α; tight junction
    DOI:  https://doi.org/10.1080/02656736.2025.2559022
  3. J Biochem Mol Toxicol. 2025 Sep;39(9): e70474
    Telmisartan Ameliorates Blood-Brain Barrier Disruption in a High-Salt Diet Mouse Model.
    Zhanhai He, Jinqiu Gao, Huaihua Guo.
      The disruption of the blood-brain barrier (BBB) in hypertension is a critical pathophysiological event characterized by an increase in barrier permeability, which can potentially lead to severe neurological complications. Telmisartan, an angiotensin II receptor antagonist (ARB), is widely prescribed for the management of hypertension. However, there is limited literature on the specific effects of Telmisartan on BBB disruption associated with high-salt diet (HSD)-induced changes. In this study, a salt-induced hypertensive state was induced in mice using a HSD to investigate the effects of telmisartan on BBB disruption associated with HSD. Our recent findings indicate that Telmisartan mitigates brain vascular endothelial inflammation and reduces BBB permeability in HSD-treated mice. Specifically, it downregulates the messenger RNA (mRNA) and protein expression levels of intercellular adhesion molecule-1 (ICAM-1) and endothelial selectin (E-selectin). Additionally, Telmisartan inhibits BBB permeability as evidenced by reduced extravasation of Evans blue dye and restores the expression of Claudin-1, a crucial tight junction (TJ) protein. In vitro studies further support these findings, demonstrating that Telmisartan effectively reduces Angiotensin II-induced permeability in human brain microvascular endothelial cells (HBMECs). Moreover, Telmisartan treatment leads to an increase in trans-endothelial electrical resistance (TEER), indicative of improved barrier function. It also restores the expression of Claudin-1, prevents endothelial dysfunction, and activates the Wnt/β-catenin signaling pathway. Notably, silencing the β-catenin pathway abrogates the beneficial effects of Telmisartan, suggesting that the protective actions of Telmisartan on BBB integrity in HSD-induced conditions are mediated through the activation of the Wnt/β-catenin signaling pathway. These results collectively suggest that Telmisartan not only effectively manages HSD-induced hypertension but also exerts neuroprotective effects by preserving BBB integrity. This dual functionality positions Telmisartan as a potentially valuable therapeutic agent for patients at risk for neurological complications due to HSD-induced BBB disruption.
    Keywords:  blood‐brain barrier; claudin‐1; high‐salt diet; telmisartan; β‐catenin
    DOI:  https://doi.org/10.1002/jbt.70474
  4. Neurosci Bull. 2025 Sep 18.
    Endothelial GATAD1 Exacerbates Blood-brain Barrier Dysfunction in Ischemic Stroke through Caveolae-mediated Transcytosis.
    Lizhen Fan, Hui Liu, Shanshan Li, Lingling Li, Zhi Zhang, Pinyi Liu, Haiyan Yang, Shengnan Xia, Xiang Cao, Chun Wang, Yun Xu.
      Blood-brain barrier (BBB) dysfunction represents a critical pathological manifestation in exacerbating ischemic stroke, contributing to neuronal death, edema formation, and unfavorable clinical outcomes. GATA zinc finger domain-containing 1 (GATAD1) is recognized as a critical transcription factor in cardiac development and cardiovascular disease. However, the role of GATAD1 in regulating BBB function and ischemic stroke remains elusive. Here, we found that GATAD1 was upregulated in cerebral endothelial cells (ECs) following ischemic stroke in mice. EC-specific Gatad1 deficiency demonstrated remarkable neuroprotection, manifested by reduced infarct volumes, ameliorated BBB dysfunction, and improved neurological outcomes following experimental stroke. Mechanistic investigations revealed that GATAD1 was involved in regulating CD36 expression, thereby modulating caveolae-mediated transcytosis in cerebral ECs. These findings established GATAD1 as a novel regulator of BBB permeability and a potential therapeutic target for ischemic stroke intervention.
    Keywords:  Blood-brain barrier; GATAD1; Ischemic stroke; Transcytosis
    DOI:  https://doi.org/10.1007/s12264-025-01507-z
  5. Brain Res Bull. 2025 Sep 12. pii: S0361-9230(25)00360-0. [Epub ahead of print] 111548
    Stress-Induced Regional Characteristics of the Blood-Brain Barrier.
    Mao-Yang Zhou, Fang Xie, Yun Zhao, Xue Wang, Zhao-Wei Sun, Ling-Jia Qian.
      The blood-brain barrier (BBB) is a neurovascular unit composed of brain microvascular endothelial cells, astrocytes, pericytes, and the basement membrane, playing a critical role in maintaining brain microenvironment homeostasis. However, exposure to external stressors can disrupt the structure and function of the BBB, leading to microenvironmental imbalances and the onset of various neurological disorders. Notably, the impact of stress on the BBB exhibits significant regional heterogeneity across different brain regions, influenced by factors such as the structural and functional characteristics of brain regions, modalities and duration of stress, and sex differences. In recent years, advancements in high-throughput technologies, including single-cell RNA sequencing and spatial transcriptomics, have gradually revealed the molecular features underlying the regional heterogeneity of the BBB under various stress conditions. This review provides a comprehensive overview of the structure and function of the BBB, elaborates the role of BBB in the progression and treatment of neurological disorders, summarizes recent research on stress-induced regional heterogeneity in BBB alterations, and integrates potential contributing factors and the underlying mechanisms. Besides, this review outlines the current applications of new technologies in BBB heterogeneity-related research and the potential values of BBB heterogeneity in clinical therapy, offering new insights and strategies for the diagnosis and treatment of neurological disorders.
    Keywords:  BBB; neurological disorders; regional heterogeneity; stress
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111548
  6. Theranostics. 2025 ;15(17): 9221-9239
    Neutrophil extracellular traps induce endothelial damage and exacerbate vasospasm in traumatic brain injury.
    Jinchao Wang, Lei Li, Jianye Xu, Dilmurat Gheyret, Kaiji Li, Xu Zhang, Haoran Jia, Ye Tian, Xiao Liu, Shenghui Li, Guili Yang, Yalong Gao, Ruilong Peng, Huajie Liu, Bin Liu, Jianfeng Zhuang, Cong Wang, Xin Chen, Yafan Liu, Bo Chen, Chuan Huang, Yuhan Li, Xin Chen, Jianning Zhang, Shu Zhang.
      Cerebral vasospasm (CVS) critically exacerbates secondary brain injury following traumatic brain injury (TBI). Understanding the underlying mechanisms is essential for developing targeted interventions. Methods: We developed a comprehensive murine multimodal imaging platform to evaluate CVS cerebral perfusion, and blood-brain barrier (BBB) integrity, integrating in vivo multiphoton microscopy, magnetic resonance angiography, carotid Doppler ultrasound, and laser speckle contrast imaging with molecular assays and functional assessments. Additionally, we comprehensively analyze single-cell RNA (TBI vs Sham) and bulk-RNA data (NETs-treated vs Control), delineating NETs-driven endothelial injury signatures. Finally, we explored the roles of PAD4-/-, TLR4 inhibition and TREM1 blockade in blocking NETs-induced endothelial injury and CVS, validating key therapeutic targets. Results: Our findings reveal that neutrophil extracellular traps (NETs) stimulate endothelial cells, promoting intracellular accumulation of TREM1, which forms a stable complex with NF-κB. This complex synergistically amplifies TLR4-mediated inflammatory responses, constituting a novel mechanism by which NETs aggravate endothelial injury and vasospasm after TBI. Preclinical interventions aimed at inhibiting NET formation or blocking TREM1 signaling significantly reduced neuroinflammation, cerebral edema, and CVS. Conclusions: These findings identify TREM1 as a promising therapeutic target and illuminate a NET-driven crosstalk between vascular dysfunction and inflammatory cascades in the context of TBI, offering novel translational insights for mitigating secondary brain injury.
    Keywords:  Endothelial dysfunction; Neutrophil extracellular traps; TREM1; Traumatic brain injury; Vascular spasm
    DOI:  https://doi.org/10.7150/thno.115746
  7. Neurol Neurochir Pol. 2025 Sep 19.
    Blood-brain barrier-associated serum proteins in epilepsy - clinical and diagnostic implications.
    Daniel Matovu.
      
    Keywords:  S100B; biomarkers; blood-brain barrier; epilepsy; matrix metalloproteinases; neuroinflammation
    DOI:  https://doi.org/10.5603/pjnns.107937
  8. Neurosci Bull. 2025 Sep 17.
    Astrocytic Cannabinoid Receptor 1 Governs Stress Resilience by Orchestrating Blood-Brain Barrier Integrity.
    Xiaopeng Ding, Yulan Li.
      
    DOI:  https://doi.org/10.1007/s12264-025-01514-0
  9. Bio Protoc. 2025 Aug 05. 15(15): e5410
    Isolation and Imaging of Microvessels From Brain Tissue.
    Josephine K Buff, Carolyn R Bertozzi, Tony Wyss-Coray, Sophia M Shi.
      Proper brain function depends on the integrity of the blood-brain barrier (BBB), which is formed by a specialized network of microvessels in the brain. Reliable isolation of these microvessels is crucial for studying BBB composition and function in both health and disease. Here, we describe a protocol for the mechanical dissociation and density-based separation of microvessels from fresh or frozen human and murine brain tissue. The isolated microvessels retain their molecular integrity and are compatible with downstream applications, including fluorescence imaging and biochemical analyses. This method enables direct comparisons across species and disease states using the same workflow, facilitating translational research on BBB biology. Key features • The protocol employs mechanical dissociation and density-based separation to isolate microvessels from brain tissues. • The protocol was used to study molecular changes in brain microvessels in neurodegeneration and aging. • Validated downstream applications of this method include fluorescence imaging, RNA sequencing, proteomics, western blotting, and ELISA. • The protocol can be applied to fresh and frozen human and murine brain samples.
    Keywords:  Aging; Blood–brain barrier; Brain endothelial cells; Microvessel isolation; Neurodegeneration; Vasculature
    DOI:  https://doi.org/10.21769/BioProtoc.5410
  10. J Neurosci Res. 2025 Sep;103(9): e70081
    Characterization of a Ferret Model of Traumatic Brain Injury due to Under-Vehicle Blast, Controlled Cortical Impact, or Blast Plus Impact.
    Molly J Goodfellow, Amanda L Hrdlick, Boris Piskoun, Julie L Proctor, Parisa Rangghran, Michael C Shaughness, Alexandra Vesselinov, Su Xu, Rao P Gullapalli, Ulrich H Leiste, William L Fourney, Catriona H T Miller, Jody C Cantu, Gary Fiskum.
      Under-vehicle blast (UVB) generated from landmines is a unique traumatic brain injury (TBI) mechanism affecting warfighters. UVB hyperacceleration can result in injury independent of impact; however, a secondary impact injury can also occur. To date, translation of findings from rodent TBI models to improved patient outcomes has been unsuccessful, perhaps due to neuroanatomical differences between humans and rodents, including white-to-gray matter ratio and cortical gyrification. To address this modeling difference, a UVB model was developed in ferrets, the brains of which more closely resemble humans. Male ferrets underwent UVB-alone (Blast), controlled cortical impact (CCI)-alone, combined UVB + CCI (BCCI), or craniotomy (Sham) procedures. Neurobehavioral assays were optimized and used to assess mood, memory, and motor control. Blast and BCCI ferrets underwent neuroimaging at baseline and 7 days post-injury. All ferrets were euthanized by terminal perfusion with paraformaldehyde on day 7 for histologic analysis. Results indicate that UVB alters cortical metabolites and induces blood-brain barrier (BBB) disruption. CCI leads to BBB disruption and cortical diffuse axonal injury, but this is not exacerbated by combination with UVB. BCCI does result in several alterations in key cortical metabolites indicative of increased neuronal injury, oxidative stress, and glial activation as well as impaired neurotransmission and energy generation. Additionally, BCCI significantly increases hyperactivity and impairs spatial memory. Anxiety-like behavior, mood, and motor function approached statistical significance. Taken together, we provide a military-relevant model of UVB in a gyrencephalic animal, the ferret, that may be applied in future investigations into TBI pathophysiology and potential treatment.
    Keywords:  axonal injury; blood–brain barrier; gyrencephalic; inflammation
    DOI:  https://doi.org/10.1002/jnr.70081
  11. J Control Release. 2025 Sep 11. pii: S0168-3659(25)00838-7. [Epub ahead of print]387 114226
    Intravenous lipid-siRNA conjugate mediates gene silencing at the blood-brain barrier and blood-CSF barrier.
    Alexander G Sorets, Katrina R Schwensen, Nora Francini, Andrew Kjar, Sarah Lyons, Joshua C Park, Dillon Palmer, Adam M Abdulrahman, Rebecca P Cowell, Ketaki A Katdare, Ella N Hoogenboezem, Angela Wang, Alexander P Ligocki, Rebecca J Embalabala, Neil Dani, Craig L Duvall, Ethan S Lippmann.
      Barriers of the central nervous system (CNS), such as the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), regulate the two-way exchange of material between the blood and CNS. While the BBB and BCSFB can become dysfunctional in patients with chronic CNS diseases, few studies have focused on strategies for targeting these interfaces. Here, we showed that an intravenously administered lipid-siRNA conjugate was delivered to and silenced genes within brain endothelial cells and choroid plexus epithelial cells, which comprise the BBB and BCSFB, respectively. A single intravenous dose of lipid-siRNA conjugate was delivered to ∼100 % of brain endothelial cells and major choroid plexus cell types, without substantial delivery into brain parenchymal tissue. Sustained mRNA and protein silencing was achieved in both brain endothelial cells and bulk choroid plexus tissues. Moreover, single cell RNA sequencing demonstrated gene knockdown in capillaries, venous endothelial cells, and choroid plexus epithelial cells without silencing genes in parenchymal cell populations. Collectively, this work establishes an effective nonviral framework to mediate gene inhibition in the brain barriers.
    Keywords:  Blood-brain barrier; Choroid plexus; Gene therapy; siRNA
    DOI:  https://doi.org/10.1016/j.jconrel.2025.114226
  12. bioRxiv. 2025 Sep 03. pii: 2025.08.28.672885. [Epub ahead of print]
    A physiological microfluidic blood-brain-barrier model for in vitro study of nanoparticle trafficking and accumulation.
    Bryan B Nguyen, Neona M Lowe, Sophia Kellogg, Kuan-Wei Huang, Hannah O'Toole, Elizabeth J Hale, Venktesh S Shirure, Bhupinder S Shergill, Steven C George, Randy P Carney.
      Although the blood-brain barrier (BBB) restricts passage of most molecules, various naturally occurring and synthetic nanoparticles are nonetheless found within the brain parenchyma. To study the mechanisms underlying this phenomenon, we developed a microfluidic BBB model (mBBB) using human cerebral microvascular endothelial cells (HCMECs) in direct contact with primary human astrocytes and pericytes within a physiologically relevant extracellular matrix. The horizontal architecture enables high-resolution imaging across the full barrier interface and allows direct assessment of nanoparticle transport and accumulation. This in vitro platform recapitulates key features of the BBB, including selective permeability, junctional protein expression, and receptor-mediated uptake pathways. Using this system, the trafficking and accumulation of structurally distinct nanoparticles, including liposomes, nanoplastics, and extracellular vesicles (EVs), were compared. Among these, heterologous EVs exhibit the highest transport efficiency. Analysis of nanoparticle properties suggest that ligand presentation and membrane composition, rather than size or stiffness, primarily govern BBB penetration. The mBBB platform provides a high-throughput, imaging-based framework to systematically interrogate nanoparticle trafficking across the BBB and offers a translational tool for both drug delivery and neurotoxicity screening.
    Keywords:  exosomes; extracellular vesicles; liposomes; macropinocytosis; nanoplastics; non-animal models; receptor mediated transcytosis
    DOI:  https://doi.org/10.1101/2025.08.28.672885
  13. Front Cell Neurosci. 2025 ;19 1656777
    Early olfactory dysfunction in experimental autoimmune encephalomyelitis reflects transient brain barrier breach and initiation of neuroinflammation in the olfactory bulb.
    Andjela Stekic, Milorad Dragic, Ivana Stevanovic, Marina Zaric Kontic, Marija Adzic Bukvic, Sanja Dacic, Milica Ninkovic, Nadezda Nedeljkovic.
      Olfactory dysfunction is increasingly recognized as an early, non-motor manifestation of multiple sclerosis (MS), but the mechanisms underlying its occurrence remain unclear. Using the rat model of experimental autoimmune encephalomyelitis (EAE), we investigated the temporal relationship between olfactory impairment, neuroinflammation, barrier integrity, and adenosine signaling in the olfactory bulb (OB) in the early stage of EAE. The study showed that more than two-thirds of EAE animals exhibited significant deficits in the buried food test as early as 3 days post-immunization (dpi), which preceded the first motor symptoms by several days. Open field test confirmed that these olfactory deficits were not due to impaired locomotion. Transient breach to the OB tissue barrier was demonstrated at 3-5 dpi by increased FITC-dextran penetration and peripheral monocyte/macrophage infiltration into the lateral aspect of the OB. The breach coincided with activation of microglia in the outer nerve layer on the lateral aspect of the OB. Oxidative stress, including elevated malondialdehyde, nitric oxide, and superoxide ion levels along with a depleted antioxidant defense system, indicated a redox imbalance, while a transient increase in neurofilament light chain serum levels at 3 dpi indicated acute neuroaxonal injury and barrier disruption at early stage EAE. At the molecular level, the simultaneous upregulation of CD73 and adenosine A1/A2A receptors along the pial surface and in the olfactory nerve layer suggested enhanced adenosine signaling in early barrier modulation. Spatial mapping of FITC-dextran penetration, peripheral infiltrates, and microglia activation indicated access of immune cells from the subarachnoid space into the OB parenchyma. Overall, these results demonstrate that the OB is a permissive entry zone for autoreactive immune cells in the OB in early stages of EAE, highlighting olfactory and behavioral testing as promising tools for early detection and monitoring of MS.
    Keywords:  CNS barriers; MS/EAE; adenosine signaling; olfactory bulb; olfactory dysfunction; subarachnoid space
    DOI:  https://doi.org/10.3389/fncel.2025.1656777
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