Purinergic P2Y₆ receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II-induced hypertension

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 b-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 vascularsmoothmuscle 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.