ArticleTranslational stroke research2022
Compartmentalized Actions of the Plasminogen Activator Inhibitors, PAI-1 and Nsp, in Ischemic Stroke.
Article in Translational stroke research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 37 citations in OpenAlex.
- Ginkgo biloba L. in preventing cardiovascular disease: pharmacological effects, mechanism of action, and therapeutic potential.Acta pharmacologica Sinica · 2026Review
- Knockdown of endothelial Serpine1 improves stroke recovery by attenuating peri-infarct blood flow and blood-brain barrier disruption.Cell death & disease · 2026Article
- Principal Component-Based Comprehensive Physical Health Score Associates With Long-Term Death in Patients With Ischemic Stroke.Journal of the American Heart Association · 2026Article
- Advances in the Research of Hypoxia-Inducible Factor-1Alpha and Plasminogen Activator Inhibitor-1 in Vascular-Related Diseases.Journal of clinical medicine research · 2026Review
- Harnessing extracellular vesicles for ischemic stroke management.Regenerative biomaterials · 2026Review
- Elevated serum plasminogen activator inhibitor-1 is associated with seizure burden, drug resistance, and neuroinflammatory markers in pediatric epilepsy.Frontiers in pediatrics · 2026Article
- The Role of Blood-Brain Barrier Disruption in Epilepsy: Mechanisms and Consequences.Neurology international · 2025Review
- Targeting Plasminogen Activator Inhibitor-1 with a Novel Small Molecule Inhibitor Attenuates Lung Fibrosis.Research square · 2025Article
- Network pharmacology analyses and corresponding validation of the mechanistic effects of Yangyin Tongnao Granules in ischemic stroke.Scientific reports · 2025Article
- Targeting autophagy and plasminogen activator inhibitor-1 increases survival and remodels the tumor microenvironment in glioblastoma.Journal of experimental & clinical cancer research : CR · 2025Article
- PA System in the Pathogenesis of Ischemic Stroke.Arteriosclerosis, thrombosis, and vascular biology · 2025Review
- The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity.Journal of neuroinflammation · 2025Article
- Experimental and clinical tests of FDA-approved kinase inhibitors for the treatment of neurological disorders (update 2024).Exploration of drug science · 2025Article
- Plasminogen activator inhibitor-1 mediates cerebral ischemia-induced astrocytic reactivity.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2025Article
- Thrombolysis exacerbates cerebrovascular injury after ischemic stroke via a VEGF-B dependent effect on adipose lipolysis.bioRxiv : the preprint server for biology · 2024Article
- Neuroserpin and Extracellular Vesicles in Ischemic Stroke: Partners in Neuroprotection?Aging and disease · 2024Review
- Analysis of ischemic stroke-mediated effects on blood-brain barrier properties along the arteriovenous axis assessed by intravital two-photon imaging.Fluids and barriers of the CNS · 2024Article
- The Janus face of endogenous neuronal tPA: promoting self-protection and worsening the death of neighboring neurons.Cell death & disease · 2024Article
- Magnetically powered microwheel thrombolysis of occlusive thrombi in zebrafish.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Preclinical evaluation of ZL006-05, a new antistroke drug with fast-onset antidepressant and anxiolytic effects.Stroke and vascular neurology · 2023Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Tissue plasminogen activator (tPA) is a multifunctional protease. In blood tPA is best understood for its role in fibrinolysis, whereas in the brain tPA is reported to regulate blood-brain barrier (BBB) function and to promote neurodegeneration. Thrombolytic tPA is used for the treatment of ischemic stroke. However, its use is associated with an increased risk of hemorrhagic transformation. In blood the primary regulator of tPA activity is plasminogen activator inhibitor 1 (PAI-1), whereas in the brain, its primary inhibitor is thought to be neuroserpin (Nsp). In this study, we compare the effects of PAI-1 and Nsp deficiency in a mouse model of ischemic stroke and show that tPA has both beneficial and harmful effects that are differentially regulated by PAI-1 and Nsp. Following ischemic stroke Nsp deficiency in mice leads to larger strokes, increased BBB permeability, and increased spontaneous intracerebral hemorrhage. In contrast, PAI-1 deficiency results in smaller infarcts and increased cerebral blood flow recovery. Mechanistically, our data suggests that these differences are largely due to the compartmentalized action of PAI-1 and Nsp, with Nsp deficiency enhancing tPA activity in the CNS which increases BBB permeability and worsens stroke outcomes, while PAI-1 deficiency enhances fibrinolysis and improves recovery. Finally, we show that treatment with a combination therapy that enhances endogenous fibrinolysis by inhibiting PAI-1 with MDI-2268 and reduces BBB permeability by inhibiting tPA-mediated PDGFRα signaling with imatinib significantly reduces infarct size compared to vehicle-treated mice and to mice with either treatment alone.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.