Atherosclerosis is a chronic inflammatory disease of the vascular wall, in large part initiated by accumulation of cholesterol‐laden macrophages (foam cells) in the walls of large and medium arteries, without adequate removal of cholesterol by high‐density lipoproteins. These lipid deposits promote an inflammatory response and the formation of atherosclerotic plaques that damage the vascular wall and can be further complicated by plaque disruption and thrombosis. The molecular mechanisms controlling atherosclerosis are sensitive to lipids and to their interactions with blood cells (platelets and immune cells), vascular cells (endothelial cells and smooth muscle cells), and peripheral cells, such as enterocytes, hepatocytes, and adipocytes, governing lipid entry, storage, and elimination within the body. This involves purinergic P2Y receptors particularly in signaling favoring inflammation and thromboses in the artery wall. However, these receptors can also promote antiatherogenic effects. This is because they are part of the molecular mechanisms determining cellular events and the disruption of which relates to atheroma formation such as the restoration of vascular endothelial function and the efflux of excess cholesterol from plaque followed by cholesterol removal via hepatobiliary lipid secretion.

We replace these different roles of P2Y receptors in atherosclerosis and specifically address recent observations determining their potential role in the regulation of both lipid and vascular homeostasis. Understanding these new functions would help in the discovery of new molecular targets for preventing atherosclerosis development. WIREs Membr Transp Signal 2012, 1:743–754. doi: 10.1002/wmts.66

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