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Updated: Jul 16, 2026
Quantification of Neurovascular Protection Following Repetitive Hypoxic Preconditioning and Transient Middle Cerebral Artery Occlusion in Mice
Published on: May 4, 2015
Activation of the annexin 1 counter-regulatory circuit affords protection in the mouse brain microcirculation
Felicity N E Gavins1, Jesmond Dalli, Roderick J Flower
1The William Harvey Research Institute, Barts and The London, Charterhouse Sq., London, EC1M 6BQ, UK.
Abstract:
The purpose of this study was to investigate the role of the homeostatic antiinflammatory axis centered on annexin 1 (AnxA1) in cerebral microvascular dysfunction and tissue injury associated with middle cerebral artery (MCA) occlusion and reperfusion. Intravital fluorescence microscopy was used to visualize the mouse cerebral microcirculation: AnxA1 null mice exhibited more white blood cell adhesion in cerebral venules than their wild-type counterparts, and this was accompanied by a larger cerebral infarct vol and worse neurological score. All parameters were rescued by delivery of human recombinant AnxA1. To further explore these findings using pharmacological tools, the effect of a short AnxA1 peptidomimetic was tested. When given during the reperfusion phase, peptide Ac2-26 produced similar cerebroprotection, which was associated with a marked attenuation of cell adhesion and markers of inflammation as measured in tissue homogenates. The pharmacological effects of peptide Ac2-26 occurred via receptors of the formyl-peptide receptor (FPR) family, most likely FPR-rs2, as deduced by displacement assays with transfected cells and in vivo experiments with transgenic mice and receptor antagonists. Our findings indicate that the endogenous antiinflammatory circuit centered on AnxA1 produces significant cerebral protection, and that these properties might have therapeutic potential for stroke treatment.
Insights
Annexin 1 (AnxA1) plays a crucial role in protecting the brain from stroke injury by reducing inflammation and microvascular dysfunction. Therapeutic strategies targeting this pathway show promise for stroke treatment.
Area of Science:
- Neuroscience
- Immunology
- Cardiovascular Research
Background:
- Cerebral microvascular dysfunction and tissue injury are significant consequences of middle cerebral artery (MCA) occlusion and reperfusion.
- The homeostatic anti-inflammatory axis involving annexin 1 (AnxA1) is a potential target for therapeutic intervention in stroke.
Purpose of the Study:
- To investigate the role of the annexin 1 (AnxA1) anti-inflammatory axis in cerebral microvascular dysfunction and tissue injury following MCA occlusion and reperfusion.
- To evaluate the therapeutic potential of AnxA1 and its peptidomimetics in a mouse model of ischemic stroke.
Main Methods:
- Intravital fluorescence microscopy was employed to visualize mouse cerebral microcirculation.
- AnxA1 null mice and wild-type littermates were used to assess the impact of AnxA1 deficiency on stroke outcomes.
- Cerebroprotection was evaluated following administration of human recombinant AnxA1 and a peptidomimetic (Ac2-26).
- Formyl-peptide receptor (FPR) involvement was investigated using transfected cells, transgenic mice, and receptor antagonists.
Main Results:
- AnxA1 null mice exhibited increased white blood cell adhesion, larger infarct volumes, and worse neurological scores compared to wild-type mice.
- Administration of recombinant AnxA1 or the Ac2-26 peptidomimetic rescued these parameters, demonstrating significant cerebroprotection.
- The protective effects of Ac2-26 were mediated through the formyl-peptide receptor (FPR) family, likely FPR-rs2.
Conclusions:
- The endogenous anti-inflammatory circuit centered on AnxA1 provides significant protection against cerebral ischemia-reperfusion injury.
- Targeting the AnxA1 pathway, potentially with peptidomimetics like Ac2-26, holds therapeutic promise for stroke treatment.
