Endothelium‐dependent relaxation evoked by ATP and UTP in the aorta of P2Y₂‐deficient mice

Abstract

1 Based on pharmacological criteria, we previously suggested that in the mouse aorta, endotheliumdependent relaxation by nucleotides is mediated by P2Y 1 (adenosine diphosphate (ADP)), P2Y 2 (adenosine triphosphate (ATP)) and P2Y 6 (uridine diphosphate (UDP)) receptors. For UTP, it was unclear whether P2Y 2 , P2Y 6 or yet another subtype was involved. Therefore, in view of the lack of selective purinergic agonists and antagonists, we used P2Y 2 -deficient mice to clarify the action of UTP. 2 Thoracic aorta segments (width 2 mm) of P2Y 2 -deficient and wild-type (WT) mice were mounted in organ baths to measure isometric force development and intracellular calcium signalling. 3 Relaxations evoked by ADP, UDP and acetylcholine were identical in knockout and WT mice, indicating that the receptors for these agonists function normally. 4 P2Y 2 -deficient mice showed impaired ATP-and adenosine 5 0 [g-thio] triphosphate (ATPgS)-evoked relaxation, suggesting that in WT mice, ATP and ATPgS activate predominantly the P2Y 2 subtype. 5 The ATP/ATPgS-evoked relaxation and calcium signals in the knockout mice were partially rescued by P2Y 1 , as they were sensitive to 2 0 -deoxy-N 6 -methyladenosine 3 0 ,5 0 -bisphosphate (MRS2179), a P2Y 1 -selective antagonist. 6 In contrast to ATP, the UTP-evoked relaxation was not different between knockout and WT mice. Moreover, the action of UTP was not sensitive to MRS2179. Therefore, the action of UTP is probably mediated mainly by a P2Y 6 (like) receptor subtype. 7 In conclusion, we demonstrated that ATP-evoked relaxation of the murine aorta is mainly mediated by P2Y 2 . But this P2Y 2 receptor has apparently no major role in UTP-evoked relaxation. The vasodilator effect of UTP is probably mediated mainly by a P2Y 6 (like) receptor.

Knockout Mice Reveal a Role for P2Y6 Receptor in Macrophages, Endothelial Cells, and Vascular Smooth Muscle Cells

“…However, recent studies on the mouse aorta revealed in an unexpected way that although the endotheliumdependent relaxation by ATP was severely decreased in P2Y 2 Ϫ/Ϫ mice, the relaxing effect of UTP was maintained, indicating the involvement of another receptor (Guns et al, 2006). This receptor might be P2Y 6 because UDP induced a relaxing effect on the mouse aorta with pharmacological features compatible with that receptor (Guns et al, 2005).…”

“…Furthermore, UDP is a growth factor for aortic smooth muscle cells in vitro (Hou et al, 2002). UDP induced an endothelium-dependent relaxation of the mouse aorta, which, like a similar action of UTP, was maintained in P2Y 2 Ϫ/Ϫ mice, suggesting the possible involvement of the P2Y 6 receptor (Guns et al, 2005(Guns et al, , 2006.…”

Reduced Atherosclerotic Lesions in P2Y 1 /Apolipoprotein E Double-Knockout Mice

“…Such a dual role has already been reported for another P2Y receptor subtype, P2Y 2 . This receptor contributes to endothelium-dependent relaxation 39 and to the expression of VCAM-1, which mediates the adhesion of monocytes to vascular endothelium. 40 The atherosclerotic lesions of P2Y 1 Ϫ/Ϫ /ApoE Ϫ/Ϫ mice also contained fewer smooth muscle cells than those of ApoE Ϫ/Ϫ mice, indicating that P2Y 1 receptor deficiency might influence the behavior of these cells.…”

Association of the Purinergic Receptor P2Y, G-Protein Coupled, 2 (P2RY2) Gene With Myocardial Infarction in Japanese Men

“…Evidence from both basic research and clinical studies indicates that purinergic signaling plays an important role in the atherosclerotic process. Guns et al found that in the aorta of P2Y2-knockout mice, there was inhibition of the ATP-endothelium-dependent relaxation, 9 which substantiates the role of P2RY2 in endothelial dysfunction. A recent study also reported that upregulation and activation of P2RY2 in rabbit arteries mediates the intimal hyperplasia that accompanies atherosclerosis, 10 further confirming a direct pathological role for P2RY2.…”