Language
English
Publication Date
11-1-2025
Journal
Pharmacological Research
DOI
10.1016/j.phrs.2025.108012
PMID
41201506
Abstract
Vascular calcification (VC) is a major contributor to cardiovascular morbidity and mortality, particularly in patients with chronic kidney disease (CKD). Adenosine 2 A receptor (ADORA2A) is highly expressed in vascular cells and implicated in cardiovascular disease; however, its specific role in VC pathogenesis remains unclear. Here, we investigated the role of ADORA2A using in vitro (vascular smooth muscle cells; VSMCs), ex vivo (mouse aortic rings), and in vivo (5/6th nephrectomy with high phosphate and cholecalciferol) models of VC. The ADORA2A expression was significantly upregulated in calcified human and murine aortic tissues, as well as in VSMCs, under osteogenic conditions. Genetic deletion of Adora2a (global or VSMC-specific) or pharmacological antagonism of ADORA2A markedly attenuated aortic calcification and the expression of osteogenic markers in vivo. Consistent findings were observed in in vitro and ex vivo models. Conversely, ADORA2A overexpression exacerbated the osteogenic differentiation and calcification of VSMCs. Mechanistically, ADORA2A promoted VSMC osteogenic differentiation by facilitating cAMP-responsive element-binding protein 1 (CREB1) binding to the runt-related transcription factor 2 (RUNX2) promoter, thereby enhancing RUNX2 transcription and subsequent mineralization. Our findings reveal that ADORA2A drives VC through the cAMP/CREB1/RUNX2 signaling axis in VSMCs. Therefore, targeting ADORA2A represents a potential strategy for mitigating VC in CKD.
Keywords
Animals, Vascular Calcification, Receptor, Adenosine A2A, Osteogenesis, Humans, Muscle, Smooth, Vascular, Signal Transduction, Cell Differentiation, Male, Mice, Inbred C57BL, Myocytes, Smooth Muscle, Mice, Cells, Cultured, Core Binding Factor Alpha 1 Subunit, Adenosine A2 Receptor Antagonists, Mice, Knockout, Cyclic AMP Response Element-Binding Protein, ADORA2A, CKD, Osteogenic differentiation, RUNX2, Vascular calcification
Published Open-Access
yes
Recommended Citation
Zhou, Yaqi; Zhao, Dingwei; Ma, Qian; et al., "Targeting Adenosine 2A Receptor Signaling Suppresses Vascular Calcification by Restraining Smooth Muscle Osteogenic Differentiation" (2025). Faculty, Staff and Students Publications. 6454.
https://digitalcommons.library.tmc.edu/baylor_docs/6454