Abstract

Cerebral thrombosis, a major cause of ischemic stroke, involves complex cellular and molecular signaling pathways, including those mediated by G protein-coupled receptors (GPCRs) and their regulators, the $\beta$-arrestins. This study investigated the role of $\beta$-Arrestin-2 ($\beta$-Arr2) in both cellular survival and in vivo stroke pathology. Our primary objective was to determine the influence of $\beta$-Arr2 gene knockout on the viability of cultured astrocytes following exposure to thrombin, a key pro-thrombotic and pro-inflammatory signaling molecule. Astrocytes, critical for maintaining the blood-brain barrier and neuronal support, were isolated from wild-type and $\beta$-Arr2 knockout mice. In parallel, we assessed the long-term neurological and histological aftereffects of induced cerebral thrombosis in $\beta$-Arr2 knockout mice compared to controls. In vitro results demonstrated that $\beta$-Arr2 deficiency significantly reduced astrocyte survival and increased apoptotic markers following thrombin challenge, suggesting a protective role for $\beta$-Arr2 in astrocyte membrane signaling and stress response. Correspondingly, in vivo analysis revealed that $\beta$-Arr2 knockout mice exhibited larger infarct volumes, exacerbated neurological deficits, and increased glial scarring in the chronic phase following cerebral thrombosis. These findings highlight $\beta$-Arr2 as a critical modulator of cellular resilience in the neurovascular unit and suggest that targeting $\beta$-Arr2 signaling pathways could represent a novel therapeutic strategy for mitigating the long-term consequences of ischemic stroke.