Endothelial adenosine receptor 2A loss alleviates diabetic vascular calcification by blocking CREB1-SNAI1-driven EndMT.

Vascular calcification (VC), a common complication associated with diabetes mellitus (DM), substantially increases the risk of cardiovascular diseases and is associated with elevated mortality in individuals with DM. Endothelial-to-mesenchymal transition (EndMT) imparts phenotypic plasticity to vascular endothelial cells (VECs), granting them the potential for osteogenic differentiation, which is a crucial mechanism in regulating VC. Notably, adenosine-ADORA2A-mediated endothelial dysfunction plays a pivotal regulatory role in cardiovascular diseases. However, the specific role of endothelial ADORA2A in diabetic VC remains to be elucidated. In this study, we found that ADORA2A was upregulated in the endothelium of diabetic mice and cultured human aortic endothelial cells (HAECs) with high glucose treatment. Deletion of endothelial Adora2a or pharmacologic inhibition of ADORA2A with KW6002 attenuated EndMT, osteogenic differentiation, and calcium deposit in diabetic aortas of Ins2^Akita/+ mice. Consistently, ADORA2A knockdown or inhibition in HAECs suppressed EndMT and osteogenic differentiation in response to high glucose and other pro-calcified conditions. Mechanistically, ADORA2A induced HAECs to undergo EndMT and osteogenic differentiation by regulating the CREB1-SNAI1 axis. Collectively, our results reveal a previously unrecognized role of endothelial ADORA2A inactivation in attenuating diabetic VC via modulation of EndMT. These insights offer a compelling mechanistic rationale for leveraging ADORA2A antagonists as promising therapeutic agents against diabetic VC.