Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease–activated receptor 1
Open accessAbstract
Activated protein C (APC) is a serine protease with anticoagulant and direct cytoprotective activities. Early postischemic APC application activates the cellular protein C pathway in brain endothelium and neurons, which is neuroprotective. Whether late APC administration after a transient ischemic attack is neuroprotective and whether APC influences brain repair is not known. Here, we determined safety and efficacy of late APC and tissue-plasminogen activator (tPA) administrations in a mouse model of transient brain ischemia. tPA given at 6 h after onset of ischemia killed all mice within 2 d, whereas APC given at 6 or 24 h after ischemia onset improved significantly functional outcome and reduced spread of the ischemic lesion. At 7 d postischemia, APC multiple dosing (0.8 mg/kg, i.p.) at 6–72 or 72–144 h enhanced comparably cerebral perfusion in the ischemic border by ∼40% as shown by in vivo lectin-FITC angiography, blocked blood–brain barrier leakage of serum proteins, and increased the number of endothelial replicating cells by 4.5- to 4.7-fold. APC multidosing at 6–72 h or 72–144 h increased proliferation of neuronal progenitor cells in the subventricular zone (SVZ) by 40–50% and migration of newly formed neuroblasts from the SVZ toward the ischemic border by approximately twofold. The effects of APC on neovascularization and neurogenesis were mediated by protease-activated receptor 1 and were independent of the reduction by APC of infarction volume. Our data show that delayed APC administration is neuroprotective and mediates brain repair (i.e., neovascularization and neurogenesis), suggesting a significant extension of the therapeutic window for APC intervention in postischemic brain.
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Activated protein C enhances neurovascular interplay by stimulating endothelial proliferation and tube formation and inducing proliferation and migration of neural precursor cells via PAR1.
“The serine protease activated protein C enhances this neurovascular interplay, stimulating endothelial proliferation and tube formation60 and inducing proliferation and migration of neural precursor cells61 via protease-activated receptor 1.”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [61]
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- Authors
- Thiyagarajan, M., Fernández, J. A., Lane, S. M., Griffin, J. H., & Zlokovic, B. V.
- Affiliations
- University of Rochester Medicine (US)
- Scripps Research Institute (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-11-26
- Volume
- 28
- Issue
- 48
- Pages
- 12788-12797
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2742231
- OpenAlex
- W2065489547
- Cited by
- 105
- References
- 57
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 5 · 2022: 6 · 2021: 3 · 2020: 8 · 2019: 4 · 2018: 5 · 2017: 9 · 2016: 10 · 2015: 7 · 2014: 10 · 2013: 8 · 2012: 8
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (HL63290, HL52246, HL081528, HL31950)
- National Heart, Lung, and Blood Institute (HL081528, HL 31950, HL63290, R01HL063290, R01HL052246, HL-52246, R01HL081528, P01HL031950, R37HL052246)
- Topics
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- activated protein C, protease-activated receptor 1, transient cerebral ischemia, neurogenesis, neovascularization, subventricular zone, neural progenitor cells, neuroprotection, tissue plasminogen activator, blood-brain barrier disruption, therapeutic window, brain repair
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Cell Movement, Cerebral Arteries, Brain Ischemia, Disease Models, Animal, Enzyme Activation, Male, Mice, Inbred C57BL, Nerve Regeneration, Tissue Plasminogen Activator, Protein C, Reperfusion Injury, Treatment Outcome, Mice, Knockout, Neovascularization, Physiologic, Recovery of Function, Brain Infarction, Receptor, PAR-1, Cell Proliferation, Mice, Neurogenesis
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