Purinergic P2Y ₆ receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II–induced hypertension

Abstract

The angiotensin (Ang) type 1 receptor (AT1R) promotes functional and structural integrity of the arterial wall to contribute to vascular homeostasis, but this receptor also promotes hypertension. In our investigation of how Ang II signals are converted by the AT1R from physiological to pathological outputs, we found that the purinergic P2Y6 receptor (P2Y6R), an inflammation-inducible G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR), promoted Ang II-induced hypertension in mice. In mice, deletion of P2Y6R attenuated Ang II-induced increase in blood pressure, vascular remodeling, oxidative stress, and endothelial dysfunction. AT1R and P2Y6R formed stable heterodimers, which enhanced G protein-dependent vascular hypertrophy but reduced β-arrestin-dependent AT1R internalization. Pharmacological disruption of AT1R-P2Y6R heterodimers by the P2Y6R antagonist MRS2578 suppressed Ang II-induced hypertension in mice. Furthermore, P2Y6R abundance increased with age in vascular smooth muscle cells. The increased abundance of P2Y6R converted AT1R-stimulated signaling in vascular smooth muscle cells from β-arrestin-dependent proliferation to G protein-dependent hypertrophy. These results suggest that increased formation of AT1R-P2Y6R heterodimers with age may increase the likelihood of hypertension induced by Ang II.

Central Role of P2Y 6 UDP Receptor in Arteriolar Myogenic Tone

“…When subjected to AngII treatment (1 mg/kg per day for 3 weeks), P2ry6 −/− mice displayed reduced hypertension compared with wild-type littermates (Figure VI in the online-only Data Supplement). Resistance to AngII-dependent hypertension was recently reported, 15 consistent with a P2Y 6 receptor effect on blood pressure regulation in pathological conditions.…”

UDP-induced relaxation is enhanced in aorta from female obese Otsuka Long–Evans Tokushima Fatty rats

“…However, we cannot define which effect preferably increased NO or suppressed prostanoid productions upon MRS2578-sensitive P2Y 6 receptor stimulation by UDP. Furthermore, the possible mechanisms underlying the activation of other receptors, such as GPR17 [36], or heterodimers, such as angiotensin type 1/P2Y 6 receptors [37,38], in our findings may be related to UDP-mediated responses. Because contrasting trends are observed in UDP-induced contraction in endothelium-denuded aorta between the groups, that is, between the basal and PE-precontracted aorta, the role of P2Y 6 (probably MRS2578-sensitive receptor) in contraction may also be different between OLETF and LETO rat aortas.…”

P2Y2 and P2Y6 receptor activation elicits intracellular calcium responses in human adipose-derived mesenchymal stromal cells

“…One possible explanation for this may be that P2Y 6 receptors exist as a heterodimer, which has led to an altered agonist profile in these cells. P2Y 6 receptors have been shown to form heterodimers with other GPCRs [37,38] and heterooligomerization of other P2Y receptors can alter the agonist sensitivity of these receptors [39]. After the initial peak, blockade of the ADP response with MRS2578 leads to a decrease in the concentration of intracellular Ca 2+ to below baseline Ca 2+ levels, suggesting there is either efflux or internalisation of Ca…”