Advanced vascular lesions begin with accumulation of vast amount of foam cells that start to necrotize and initiate T-cell infiltration to the intima. T-cells, together with neutrophils, contribute to the signaling mechanism that drives the vascular smooth muscle cells (VSMC) to move into the intima. There, VSMC de-differentiate, proliferate and start secreting extracellular matrix proteins. The result of this process is a formation of a fibrous cap around the necrotic foam cell mass (reviewed in [13
]). No one has yet determined whether adenosine levels in or around the vascular lesion are elevated. On the other hand, inflammation rises as atherosclerosis progresses, and inflammatory cytokines increase expression of adenosine receptors [19
]. Indeed, studies done in mouse models lacking adenosine receptors show that the role of adenosine in atherosclerosis, whether protective or deleterious, depends on the ablated receptor.
The first glimpse of the role of adenosine in atherosclerosis started with the elimination of the A3AR on an Apolipoprotein E (ApoE) null background. ApoE KO mice are a useful model to study atherosclerosis, since mice do not naturally develop all stages of atherosclerotic lesions along the arterial tree [30
]. In the case of the A3AR, although aortic vascular smooth muscle cells exhibit decreased proliferation potential upon receptor-elimination and A3AR contributes to the process of inflammation, there is no effect on the chronic development of atherosclerosis [34
As mentioned earlier, A2AAR KO macrophages have increased foam cell formation potential and A2AAR is anti-inflammatory. It is surprising, however, that A2AAR, ApoE double KO mice on high fat diet have smaller atherosclerotic lesions, as compared to the control mice used in the study. The major contributors to this anti-atherosclerotic profile were the macrophages; in vivo these cells were highly apoptotic and vascular lesions were smaller [35•
]. Overall, elimination of the A2AAR results in increased levels of plasma cholesterol, concentrated predominantly in the LDL particles [35•
]. These findings are quite intriguing, considering that increased inflammatory state and elevated plasma cholesterol typically lead to atherosclerosis. Yet the above study shows that the A2AAR is deleterious, rather than protective against atherosclerosis. Further, in a model of restenosis post arterial angioplasty, elimination of the A2AAR results in an increase of neointima and raised the possibility that A2AAR is actually protective against vascular lesion formation [36•
]. In this case, in the A2AAR KO, there was an increase in the homing ability of leukocytes to the sub-endothelial space, which led to a consequent increase in neointima thickness [36•
]. It is quite possible that under chronic inflammation (atherosclerosis) A2AAR is harmful, but under more acute conditions (post angioplasty) it becomes protective. This defines the A2AAR signaling more complex than expected, and this receptor might be more challenging as therapeutic target in the context of vascular disease.
The role of the A2BAR in vascular diseases has also been extensively studied. As described earlier, endothelial A2BARs regulate the expression of surface adhesion molecules and improve leukocyte rolling [3
]. In a similar fashion to the A2AAR, in a model of restenosis post angioplasty, the A2BAR protects against increased neointima formation. This protective effect is due to A2BAR-mediated signals coming from bone marrow cells [3
]. Vascular smooth muscle cells lacking expression of this receptor have an increased proliferation rate [3
], and activated macrophages show an increase in levels of matrix metalloproteinase-9 (MMP-9) levels [37
]. Vascular-derived matrix metalloproteinases, such as MMP-9 play an important role in neointima formation after vascular injury and in de-stabilizing advanced atherosclerotic plaques [37
All of these in vitro and in vivo studies are consistent with a protective effect of the A2BAR against vascular diseases. In a model of atherosclerosis, where the A2BAR is eliminated in ApoE null mice, plaque formation along the aortic tree is elevated. Risk factors, such as plasma cholesterol and triglycerides, detrimental in the development of atherosclerosis, are highly augmented when this receptor is eliminated. This lipid elevation of cholesterol and triglycerides is predominantly concentrated in the very low density lipoprotein (VLDL) particles. Consistently, activation of the A2BAR with specific agonist (BAY 60-6053, Bayer, Germany) leads to reduction in lesion formation, and a decrease in synthesis and plasma levels of cholesterol and triglycerides. It is important to mention that the activation of the A2BAR is beneficial with respect to atherosclerosis and plasma lipids even during high-fat, high-cholesterol diet [2•
] (). The major organ contributing to the anti-atherosclerotic profile, in the case of this receptor, is the liver. Normally the liver expresses very little A2BAR [3
], but with high fat, high cholesterol diet the levels of A2BAR in this organ become vastly elevated [2•
]. Mechanistically, activation of the A2BAR in hepatocytes in vivo and in vitro causes a decreased activation of the transcription factor sterol regulatory element binding protein one (SREBP1), a major switch regulating lipid synthesis.
Adenosine receptors and their beneficial role in atherosclerosis and cardiovascular disease
In summary, with respect to atherosclerosis, A2BAR is protective against atherosclerosis and its activation reduces vascular lesion formation. In contrast, A2AAR elimination is protective and A3AR has no effect (). The role of A1AR in this regard is not known.