January 2020

Circulation. 2020 Jan 16. doi: 10.1161/CIRCULATIONAHA.119.043703.

Orphan G-Protein-Coupled Receptor GPRC5B Controls Smooth Muscle Contractility and Differentiation by Inhibiting Prostacyclin Receptor Signaling.

Carvalho J, Chennupati R, Li R, Günther S, Kaur H, Zhao W, Tonack S, Kurz M, Mößlein N, Bünemann M, Offermanns S, Wettschureck N.

Background: G-protein-coupled receptors (GPCRs) are important regulators of contractility and differentiation in vascular smooth muscle cells (SMC), but the specific function of SMC-expressed orphan GPCR GPRC5B is unclear. Methods: We studied the role of GPRC5B in the regulation of contractility and dedifferentiation in human and murine SMC in vitro as well as in tamoxifen-inducible, SMC-specific knockout mice (iSM-Gprc5b-KO) under conditions of arterial hypertension and atherosclerosis in vivo. Results: Mesenteric arteries from SMC-specific Gprc5b-KOs showed ex vivo significantly enhanced prostacyclin receptor (IP)-dependent relaxation, whereas responses to other relaxant or contractile factors were normal. In vitro, knockdown of GPRC5B in human aortic SMC resulted in increased IP-dependent cAMP production and consecutive facilitation of SMC relaxation. In line with this facilitation of IP-mediated relaxation, iSM-Gprc5b-KO mice were protected from arterial hypertension, and this protective effect was abrogated by IP antagonists. Mechanistically, we show that knockdown of GPRC5B increased the membrane localization of IP both in vitro and in vivo, and that GPRC5B, but not other GPCRs, physically interact with IP. Finally, we show that enhanced IP signaling in GPRC5B-deficient smooth muscle cells does not only facilitate relaxation, but also prevents dedifferentiation during atherosclerosis development, resulting in reduced plaque load and increased differentiation of SMC in the fibrous cap. Conclusions: Taken together, our data show that GPRC5B regulates vascular SMC tone and differentiation by negatively regulating IP signaling.