Upregulation of VEGFA through the adenosine A2A receptor is a crucial pathway for inhibiting pericyte apoptosis in chronic cerebral hypoperfusion
Abstract Chronic cerebral hypoperfusion (CCH) is a key factor in vascular cognitive impairment. Pericyte loss and subsequent blood-brain barrier disruption play pivotal roles in the pathogenesis of CCH-induced white matter lesions (CCH-WMLs). Previous work suggested that the adenosine A2A receptor (...
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| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
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| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-08407-2 |
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| Summary: | Abstract Chronic cerebral hypoperfusion (CCH) is a key factor in vascular cognitive impairment. Pericyte loss and subsequent blood-brain barrier disruption play pivotal roles in the pathogenesis of CCH-induced white matter lesions (CCH-WMLs). Previous work suggested that the adenosine A2A receptor (A2AR) may protect pericytes in CCH-WMLs, but the mechanisms are not fully understood. In this study, we induced CCH in Sprague‒Dawley rats via bilateral carotid artery occlusion and treated them with the A2AR agonist CGS21680 or the A2AR antagonist SCH58261. Our findings revealed that CGS21680 significantly inhibited the expression of the proapoptotic proteins BAX and Caspase 3, while SCH58261 obviously promoted it. The expression of the antiapoptotic protein Bcl-2 was markedly increased by CGS21680 in OGD-exposed pericytes. Additionally, the expression of the transcription factors Rap-1, ERK, and phosphorylated ERK also increased dramatically in OGD-exposed pericytes following CGS21680 administration. VEGFA and VEGFR2 expression was upregulated by CGS21680 and downregulated by SCH58261 in pericytes after OGD. Furthermore, VEGFA knockdown via a shRNA-expressing adenovirus counteracted the protective effect of A2AR against pericyte apoptosis following OGD. Notably, the expression of BAX and Caspase3 was significantly upregulated, and the expression of BCL-2 was markedly downregulated in OGD-exposed pericytes after Rap-1 knockdown via a shRNA-expressing adenovirus. Rap-1 suppression obviously reduced the levels of phosphorylated ERK, VEGFA and VEGFR2 in pericytes, suggesting a role for the Rap1-ERK pathway in the A2AR-induced upregulation of VEGFA expression. Overall, A2AR activation inhibits pericyte apoptosis and may exert neuroprotective effects against CCH by increasing VEGFA expression through the Rap1-ERK signaling pathway. |
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| ISSN: | 2045-2322 |