Abstract 310: Adenosine Receptor 2A-mediated Endothelial-Mesenchymal Transition Promotes Atherosclerosis

Purpose: Endothelial-mesenchymal transition (EndMT) leading to endothelial dysfunction, inflammation and disruption of endothelial barrier, promotes the development of atherosclerosis. We have previously shown that inactivation of adenosine 2A receptor (ADORA2A) inhibits the formation of atherosclerosis lesion in mice. However, the underlying mechanism has not been fully studied. Here we investigated the role of ADORA2A-drive EndMT in the development of atherosclerosis. Methods: The expression of ADORA2A in vascular endothelial cells (EC) at atheroprone regions of mouse aortas were examined by en face staining with ADORA2A and CD31 antibodies. EC-specific Adora2a knockout mice and inhibitor KW6002 were used to investigate the role of endothelial ADORA2A in EndMT and atherosclerosis in vivo . In vitro studies, the role of ADORA2A in TGFβ-1-induced EndMT was examined by Western blot, qPCR and immunostaining. Results: ADORA2A expression in ECs of lesion-prone arteries was upregulated. The formation of atherosclerotic plaques and EndMT were inhibited in endothelial Adora2a knockout mice or mice treated with antagonist KW6002. In the in vitro studies, EndMT induction of human aortic endothelial cells (HAECs) was inhibited by Adora2a knockdown and antagonist KW6002, but was promoted by adenovirus encoding Adora2a. Mechanistically, ADORA2A promoted the expression of TGFβR1/ALK5 and the activity of its downstream P-Smad2/3 signaling pathway through the cAMP/PKA/CREB signaling pathway Conclusions: ADORA2A promotes EndMT through the cAMP/PKA/CREB/ALK5 signaling pathway, resulting in increased formation of atherosclerotic lesions.