Research ArticleGPCR SIGNALING

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

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Sci. Signal.  19 Jan 2016:
Vol. 9, Issue 411, pp. ra7
DOI: 10.1126/scisignal.aac9187

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Raising blood pressure with age

Activation of angiotensin AT1 receptors in vascular smooth muscle cells by angiotensin II can trigger either proliferation or hypertrophy (the latter of which increases blood pressure), depending on age. Nishimura et al. discovered that an age-related increase in the heterodimerization of AT1 receptors with purinergic P2Y6 receptors explained the different responses to angiotensin II. Blood pressure increased to a lesser extent in response to angiotensin II in mice lacking P2Y6 receptors. Vascular smooth muscle cells from young mice had less P2Y6 receptor than those from older mice. Angiotensin II increased the proliferation of vascular smooth muscle cells from young mice but increased cell size in those from older mice by activating different signaling pathways. Thus, targeting the interaction between AT1 and P2Y6 receptors may decrease age-associated high blood pressure.

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.

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