Background—The P2Y₁ receptor plays a key role in arterial thrombosis and is widely expressed in many cell types involved in atherosclerosis. The aim of this study was to evaluate its potential involvement in the development of atherosclerotic lesions.

Methods and Results—Apolipoprotein E–deficient (ApoE^-/-) and P2Y₁^-/-/ApoE^-/- mice were maintained on regular chow for 17 or 30 weeks before analysis of atherosclerotic lesions. At 17 weeks, lesions in the aortic sinus and entire aorta were smaller in P2Y₁^-/-/ApoE^-/- compared with those in ApoE^-/- animals. At 30 weeks, the aortic sinus lesions in P2Y₁^-/-/ApoE^-/- mice were still diminished in size and displayed reduced inflammation, reflected by decreased macrophage infiltration and diminished VCAM-1 immunostaining, compared with those in ApoE^-/- mice. They also had a lower smooth muscle cell content. Unexpectedly, bone marrow transplantation showed that the absence of the P2Y₁ receptor in blood cells only led to no significant modification of the lesion compared with control ApoE^-/- reconstituted animals. Conversely, the absence of the P2Y₁ receptor except in blood cells resulted in a reduction in lesion size similar to that in control P2Y₁^-/-/ApoE^-/- reconstituted mice, pointing to a role of non–hematopoietic-derived P2Y₁ receptors, most likely the endothelial or smooth muscle cell P2Y₁ receptors. In addition, although this was not statistically significant, plasma cholesterol levels were consistently decreased in P2Y₁^-/- animals, suggesting that a modification of lipid metabolism could be responsible for the observed phenotype.

Conclusion—The P2Y₁ receptor contributes to atherosclerosis, primarily through its role in non–hematopoietic-derived cells.