Mild Hypoxia Accelerates Cerebral Cavernous Malformation Disease Through CX3CR1-CX3CL1 Signaling

Hypoxia CADASIL
DOI: 10.1161/atvbaha.123.320367 Publication Date: 2024-04-25T09:01:14Z
ABSTRACT
BACKGROUND: Heterogeneity in the severity of cerebral cavernous malformations (CCMs) disease, including brain bleedings and thrombosis that cause neurological disabilities patients, suggests environmental, genetic, or biological factors act as disease modifiers. Still, underlying mechanisms are not entirely understood. Here, we report mild hypoxia accelerates CCM by promoting angiogenesis, neuroinflammation, vascular brains mouse models. METHODS: We used genetic studies, RNA sequencing, spatial transcriptome, micro–computed tomography, fluorescence-activated cell sorting, multiplex immunofluorescence, coculture imaging techniques to reveal sustained via CX3CR1-CX3CL1 (CX3C motif chemokine receptor 1/chemokine [CX3C motif] ligand 1) signaling pathway influences cell-specific neuroinflammatory interactions, contributing heterogeneity severity. RESULTS: Histological expression profiles neurovascular lesions ( Slco1c1-iCreERT2;Pdcd10 fl/fl ; Pdcd10 BECKO ) male female mice found (12% O 2 , 7 days) disease. Our findings indicate a small reduction oxygen levels can significantly increase enhancing interactions between endothelium, astrocytes, immune cells. study indicates CX3CR1 CX3CL1 crucial maturation propensity immunothrombosis. In particular, this regulates recruitment activation microglia other cells lesions, which leads lesion growth thrombosis. human variants linked lower burden familial CCMs, proving it is modifier potential marker for aggressiveness. Moreover, monoclonal blocking antibody against reducing 1 copy Cx3cr1 gene reduces hypoxia-induced CONCLUSIONS: reveals modify neuropathology when accelerated environmental hypoxia. hypoxic environment caused balance neuroinflammation neuroprotection mediated signaling. These results establish patient stratification predictor
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (82)
CITATIONS (7)