CD69 Plays a Beneficial Role in Ischemic Stroke by Dampening Endothelial Activation

Abstract

Rationale: CD69 is an immunomodulatory molecule induced during lymphocyte activation. Following stroke, T lymphocytes upregulate CD69 but its function is unknown. Objective: We investigated whether CD69 was involved in brain damage following ischemic stroke. Methods and Results: We used adult male mice on the C57BL/6 or BALB/c backgrounds, including wild type mice and CD69-/mice, and CD69 +/+ and CD69-/lymphocyte-deficient Rag2-/mice, and generated chimeric mice. We induced ischemia by transient or permanent middle cerebral artery occlusion. We measured infarct volume, assessed neurological function, and studied CD69 expression, as well as platelet function, fibrin(ogen) deposition, and von Willebrand factor (vWF) expression in brain vessels and vWF content and activity in plasma, and performed the tail-vein bleeding test and the carotid artery FeCl3-induced thrombosis model. We also carried out primary glial cell cultures, and sorted brain CD45-CD11b-CD31 + endothelial cells for mRNA expression studies. We blocked vWF by i.v. administration of anti-vWF antibodies. CD69-/mice showed larger infarct volumes and/or worse neurological deficits than the wild type mice after ischemia. This worsening effect was not attributable to lymphocytes or other hematopoietic cells. CD69 deficiency lowered the time to thrombosis in the carotid artery despite platelet function not being affected. Ischemia upregulated Cd69 mRNA expression in brain endothelial cells. CD69-deficiency increased fibrin(ogen) accumulation in the ischemic tissue, and plasma vWF content and activity, and vWF expression in brain vessels. Blocking vWF reduced infarct volume and reverted the detrimental effect of CD69-/deficiency. Conclusion: CD69 deficiency promotes a pro-thrombotic phenotype characterized by increased vWF and worse brain damage after ischemic stroke. The results suggest that CD69 acts as a down-regulator of endothelial activation.

Stenosis coexists with compromised α1-adrenergic contractions in the ascending aorta of a mouse model of Williams-Beuren syndrome

“…Measurement of systolic blood pressure was performed in conscious WT and CD mice using the tail-cuff method (NIPREM 645; Cibertec, Madrid, Spain). The average systolic blood pressure of each mouse was determined from six consecutive measurements after habituation, as described 30 .…”

circAFF1 Aggravates Vascular Endothelial Cell Dysfunction Mediated by miR-516b/SAV1/YAP1 Axis

“…The occurrence and development of vascular endothelial injury is an important Abbreviations: AKT1, AKT serine/threonine kinase 1; CCK-8, cell counting Kit-8; CDK2, cyclin-dependent kinase 2; cDNA, complementary DNA; CI, cerebral infarction; circRNAs, circular RNAs; Ctrl, Control; FBS, fetal bovine serum; FISH, Fluorescence in situ hybridization; miRNA, microRNA; OD, optical density; PDK1, pyruvate dehydrogenase kinase 1; PI, propidium iodide; qRT-PCR, quantitative real-time polymerase chain reaction; SAV1, salvador family WW domain containing protein 1; SD, standard deviation; SDS-PAGE, Sodium dodecyl sulfate-Polyacrylamide gel electrophoresis; siRNA, small interfer RNA; tRNA, tranfer ribonucleic acid; WT, wild type; YAP1, Yes-associated protein 1. cause of many diseases, such as cardiovascular and cerebrovascular diseases, diabetes and tumors (Shan et al, 2017;Qureshi-Baig et al, 2019). Insufficient nutrient supply and hypoxia can cause myocardial infarction and stroke (Lim, 2017;Brait et al, 2019). While, bleeding can also seriously threaten human health, such as subarachnoid hemorrhage.…”

“…The occurrence and development of vascular endothelial injury is an important cause of many diseases, such as cardiovascular and cerebrovascular diseases, diabetes and tumors ( Shan et al, 2017 ; Qureshi-Baig et al, 2019 ). Insufficient nutrient supply and hypoxia can cause myocardial infarction and stroke ( Lim, 2017 ; Brait et al, 2019 ). While, bleeding can also seriously threaten human health, such as subarachnoid hemorrhage.…”

von Willebrand Factor and Platelet Glycoprotein Ib: A Thromboinflammatory Axis in Stroke

“…Recently, analogous observations were made in CD69 deficient mice (62). CD69 was identified as a negative regulator of endothelial VWF release, and in the setting of stroke, its absence resulted in a more severe stroke burden due to increased cerebral thrombosis (62).…”

“…Correspondingly, ADAMTS13 deficient mice showed an increased number of thrombi containing fibrin and VWF in the brain lesions after stroke (53). Recently, analogous observations were made in CD69 deficient mice (62). CD69 was identified as a negative regulator of endothelial VWF release, and in the setting of stroke, its absence resulted in a more severe stroke burden due to increased cerebral thrombosis (62).…”