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Updated: Mar 27, 2026
Stretch in Brain Microvascular Endothelial Cells cEND as an In Vitro Traumatic Brain Injury Model of the Blood Brain Barrier
Published on: October 26, 2013
Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier
Nanhong Lou1, Takahiro Takano1, Yong Pei1
1Center for Translational Neuromedicine, University of Rochester Medical School, Rochester, NY 14642;
Abstract:
Microglia are integral functional elements of the central nervous system, but the contribution of these cells to the structural integrity of the neurovascular unit has not hitherto been assessed. We show here that following blood-brain barrier (BBB) breakdown, P2RY12 (purinergic receptor P2Y, G-protein coupled, 12)-mediated chemotaxis of microglia processes is required for the rapid closure of the BBB. Mice treated with the P2RY12 inhibitor clopidogrel, as well as those in which P2RY12 was genetically ablated, exhibited significantly diminished movement of juxtavascular microglial processes and failed to close laser-induced openings of the BBB. Thus, microglial cells play a previously unrecognized protective role in the maintenance of BBB integrity following cerebrovascular damage. Because clopidogrel antagonizes the platelet P2Y12 receptor, it is widely prescribed for patients with coronary artery and cerebrovascular disease. As such, these observations suggest the need for caution in the postincident continuation of P2RY12-targeted platelet inhibition.
Insights
Microglia are crucial for brain repair. Their P2RY12 receptor guides cell movement to rapidly seal the blood-brain barrier after injury, a process impaired by P2RY12 inhibitors like clopidogrel.
Area of Science:
- Neuroscience
- Immunology
- Vascular Biology
Background:
- Microglia are key immune cells in the central nervous system.
- Their role in maintaining the neurovascular unit and blood-brain barrier (BBB) integrity is not well understood.
- The P2RY12 receptor's function in microglia during BBB repair is unknown.
Purpose of the Study:
- To investigate the role of microglia and the P2RY12 receptor in the structural integrity of the neurovascular unit.
- To determine if microglial P2RY12-mediated responses are essential for blood-brain barrier repair following damage.
Main Methods:
- Utilized mouse models with genetic ablation of P2RY12 and pharmacological inhibition using clopidogrel.
- Assessed microglial process dynamics using in vivo imaging techniques.
- Quantified the closure of laser-induced blood-brain barrier openings.
Main Results:
- P2RY12-mediated chemotaxis of microglial processes is essential for rapid blood-brain barrier closure.
- Mice lacking P2RY12 or treated with clopidogrel showed significantly reduced movement of juxtavascular microglial processes.
- These mice failed to effectively close laser-induced BBB openings, indicating impaired repair.
Conclusions:
- Microglia play a critical, previously unrecognized protective role in maintaining BBB integrity after cerebrovascular damage.
- Targeting P2RY12 with drugs like clopidogrel, commonly used for cardiovascular conditions, may impede essential neuroprotective mechanisms.
- Caution is advised regarding the continuation of P2RY12 inhibition post-cerebrovascular incident.
