Pericyte response to ischemic stroke precedes endothelial cell death and blood-brain barrier breakdown

Stroke is one of the leading causes of death and disability, yet the cellular response to the ischemic insult is poorly understood limiting therapeutic options. Brain pericytes are crucial for maintaining blood-brain barrier (BBB) integrity and are known to be one of the first responders to ischemic stroke. The exact timeline of cellular events after stroke, however, remains elusive. Using the permanent middle cerebral artery occlusion stroke model, we established a detailed timeline of microvascular events after experimental stroke. Our results show that pericytes respond already within 1 hour after the ischemic insult. We find that approximately 30% of the pericyte population dies as early as 1 hour after stroke, while ca 50% express markers that indicate activation. A decrease of endothelial tight junctions, signs of endothelial cell death and reduction in blood vessel length are only detected at time points after the initial pericyte response. Consistently, markers of BBB leakage are observed several hours after pericyte cell death and/or vascular detachment. Our results suggest that the pericyte response to stroke occurs early and precedes both the endothelial response and the BBB breakdown. This highlights pericytes as an important target cell type to develop new diagnostic and therapeutic tools.