Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 41, Issue 8, Pages 2090-2104Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X21992980
Keywords
Acute ischemic stroke; blood-brain barrier; small extracellular vesicles; tPA; endothelial cells
Categories
Funding
- NIH [RO1 NS111801, R56 AG055583]
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The study demonstrates that small extracellular vesicles derived from rat cerebral endothelial cells (CEC-sEVs) in combination with tissue plasminogen activator (tPA) have a positive effect on treating cerebral large vessel occlusion, reducing infarct volume, increasing recanalization, improving cerebral blood flow, and reducing blood-brain barrier leakage. This treatment also effectively suppresses a network of microRNAs and proteins that mediate thrombosis, coagulation, and inflammation.
Treatment of patients with cerebral large vessel occlusion with thrombectomy and tissue plasminogen activator (tPA) leads to incomplete reperfusion. Using rat models of embolic and transient middle cerebral artery occlusion (eMCAO and tMCAO), we investigated the effect on stroke outcomes of small extracellular vesicles (sEVs) derived from rat cerebral endothelial cells (CEC-sEVs) in combination with tPA (CEC-sEVs/tPA) as a treatment of eMCAO and tMCAO in rat. The effect of sEVs derived from clots acquired from patients who had undergone mechanical thrombectomy on healthy human CEC permeability was also evaluated. CEC-sEVs/tPA administered 4 h after eMCAO reduced infarct volume by similar to 36%, increased recanalization of the occluded MCA, enhanced cerebral blood flow (CBF), and reduced blood-brain barrier (BBB) leakage. Treatment with CEC-sEVs given upon reperfusion after 2 h tMCAO significantly reduced infarct volume by similar to 43%, and neurological outcomes were improved in both CEC-sEVs treated models. CEC-sEVs/tPA reduced a network of microRNAs (miRs) and proteins that mediate thrombosis, coagulation, and inflammation. Patient-clot derived sEVs increased CEC permeability, which was reduced by CEC-sEVs. CEC-sEV mediated suppression of a network of pro-thrombotic, -coagulant, and -inflammatory miRs and proteins likely contribute to therapeutic effects. Thus, CEC-sEVs have a therapeutic effect on acute ischemic stroke by reducing neurovascular damage.
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