Adenosine 2A receptor modulates inflammation and phenotype in experimental abdominal aortic aneurysms

Activation of the adenosine 2A receptor (A_2AR) reduces inflammation in models of acute injury but contribution in development of chronic abdominal aortic aneurysms (AAAs) is unknown. Elastase perfusion to induce AAA formation in A_2AR-knockout (A_2ARKO) and C57BL6/J wild-type (WT) mice resulted in nearly 100% larger aneurysms in A _2ARKO compared toWT at d 14 (P<0.05), with evidence of greater elastin fragmentation, more immune cell infiltration, and increased matrix metallatoproteinase (MMP) 9 expression (P<0.05). Separately, exogenous A _2AR antagonism in elastase-perfused WT mice also resulted in larger aneurysms (P<0.05), while A_2AR agonism limited aortic dilatation (P<0.05). Activated Thy-1.2⁺ T lymphocytes from WT mice treated in vitro with A_2AR antagonist increased cytokine production, and treatment with A_2AR agonist decreased cytokine production (P<0.05 for all). Primary activated CD4⁺ T lymphocytes from A_2ARKO mice exhibited greater chemotaxis (P<0.05). A_2AR antagonist increased chemotaxis of activated CD4⁺ cells from WT mice in vitro, and A_2AR agonist reduced this effect (P<0.05). A_2AR activation attenuates AAA formation partly by inhibiting immune cell recruitment and reducing elastin fragmentation. These findings support augmenting A _2AR signaling as a putative target for limiting aneurysm formation.