ArticleThe Journal of clinical investigation2023
TIMP2 ameliorates blood-brain barrier disruption in traumatic brain injury by inhibiting Src-dependent VE-cadherin internalization.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 40 citations in OpenAlex.
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- Neutrophil extracellular traps delivering lactylated S100a9 aggravate neuronal cuproptosis by regulating Ttr/Commd1/Atp7b axis after traumatic brain injury.Redox biology · 2026Article
- The potential and therapeutic advances of the integrin family in neurological disorders.Neural regeneration research · 2026Article
- Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice.Nature communications · 2026Article
- Treatment of heterotopic ossification via inhibiting the MMP-2/CDH5 axis through oral delivery of network pharmacology-predicted Chinese medicine.Materials today. Bio · 2026Article
- Innovative Biomaterials for Modulating Neuroinflammation and Promoting Repair After Traumatic Brain Injury.Pharmaceutics · 2026Review
- Microfluidic-mass spectrometry analysis of blood-brain barrier transport using engineered microparticle interfaces.Chemical science · 2026Article
- A Single Concussion in Juvenile Mice Leads to Sex Specific Acute Cerebral Vascular Dysfunction and Blood-brain Border Dysfunction.Research square · 2026Article
- Endothelial IRE1 signaling maintains blood-brain barrier integrity and limits neuroinflammation after traumatic brain injury.Cell death & disease · 2026Article
- Synergistic fusion of CD47, VE-cadherin and mussel adhesion protein promotes endothelialization and suppresses inflammation in vascular stents.Bioactive materials · 2026Article
- Brain-rejuvenating factor TIMP2 is associated with brain health and neuroprotective lifestyle in aged subjects.medRxiv : the preprint server for health sciences · 2025Article
- MRI-DTI contributes to evaluating diffuse neural injury following repetitive mild traumatic brain injury.iScience · 2025Article
- SOCS2 alleviates traumatic brain injury-induced mitochondrial damage and parthanatos in endothelial cells by inhibiting the JAK2/STAT3 signaling pathway.Metabolic brain disease · 2025Article
- Thyroid Hormone T4 Alleviates Traumatic Brain Injury by Enhancing Blood-Brain Barrier Integrity.International journal of molecular sciences · 2025Article
- Neuroprotective Effect of Rosuvastatin Calcium Combined with Hyperbaric Oxygen Mediated p38MAPK Pathway in Rats with Leukoaraiosis.Cell biochemistry and biophysics · 2025Article
- Exercise plasma improves traumatic brain injury outcomes in mice.Scientific reports · 2025Article
- NMN Supplementation Inhibits Endothelial Cell ROS-Mediated Src/Pi3k/Akt Signaling Pathway to Protect High-Altitude Blood-Retinal Barrier.Investigative ophthalmology & visual science · 2025Article
- Histidine Tag-Specific PEGylation Improves the Circulating Half-Life of TIMP2.ACS applied bio materials · 2025Article
- Activation of angiopoietin-1 signaling with engineering mesenchymal stem cells promoted efficient angiogenesis in diabetic wound healing.Stem cell research & therapy · 2025Article
- Research progress on the correlation between biological rhythms and the blood-brain barrier after ischemic stroke.Frontiers in neurology · 2025Review
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Authors and funding
10 authors at 1 institution in 1 country.
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Abstract
Blood-brain barrier (BBB) disruption is a serious pathological consequence of traumatic brain injury (TBI), for which there are limited therapeutic strategies. Tissue inhibitor of metalloproteinase-2 (TIMP2), a molecule with dual functions of inhibiting MMP activity and displaying cytokine-like activity through receptor binding, has been reported to inhibit VEGF-induced vascular hyperpermeability. Here, we investigate the ability of TIMP2 to ameliorate BBB disruption in TBI and the underlying molecular mechanisms. Both TIMP2 and AlaTIMP2, a TIMP2 mutant without MMP-inhibiting activity, attenuated neurological deficits and BBB leakage in TBI mice; they also inhibited junctional protein degradation and translocation to reduce paracellular permeability in human brain microvascular endothelial cells (ECs) exposed to hypoxic plus inflammatory insult. Mechanistic studies revealed that TIMP2 interacted with α3β1 integrin on ECs, inhibiting Src activation-dependent VE-cadherin phosphorylation, VE-cadherin/catenin complex destabilization, and subsequent VE-cadherin internalization. Notably, localization of VE-cadherin on the membrane was critical for TIMP2-mediated EC barrier integrity. Furthermore, TIMP2-mediated increased membrane localization of VE-cadherin enhanced the level of active Rac1, thereby inhibiting stress fiber formation. All together, our studies have identified an MMP-independent mechanism by which TIMP2 regulates EC barrier integrity after TBI. TIMP2 may be a therapeutic agent for TBI and other neurological disorders involving BBB breakdown.
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