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RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a G?_i2-Protein/PI3Kß/?/Nitric Oxide-Coupled Pathway.

ABSTRACT: Background: Relaxins are small peptide hormones, which are novel candidate molecules that play important roles in cardiometablic syndrome. Relaxins are structurally related to the insulin hormone superfamily, which provide vasodilatory effects by activation of G-protein-coupled relaxin receptors (RXFPs) and stimulation of endogenous nitric oxide (NO) generation. Recently, relaxin could be demonstrated to activate G_i proteins and phosphoinositide 3-kinase (PI3K) pathways in cultured endothelial cells in vitro. However, the contribution of the G_i-PI3K pathway and their individual components in relaxin-dependent relaxation of intact arteries remains elusive. Methods: We used G?_i2- (Gnai2^-/-) and G?_i3-deficient (Gnai3^-/-) mice, pharmacological tools and wire myography to study G-protein-coupled signaling pathways involved in relaxation of mouse isolated mesenteric arteries by relaxins. Human relaxin-1, relaxin-2, and relaxin-3 were tested. Results: Relaxin-2 (?50% relaxation at 10^-11 M) was the most potent vasodilatory relaxin in mouse mesenteric arteries, compared to relaxin-1 and relaxin-3. The vasodilatory effects of relaxin-2 were inhibited by removal of the endothelium or treatment of the vessels with N (G)-nitro-L-arginine methyl ester (L-NAME, endothelial nitric oxide synthase (eNOS) inhibitor) or simazine (RXFP1 inhibitor). The vasodilatory effects of relaxin-2 were absent in arteries of mice treated with pertussis toxin (PTX). They were also absent in arteries isolated from Gnai2^-/- mice, but not from Gnai3^-/- mice. The effects were not affected by FR900359 (G?_q protein inhibitor) or PI-103 (PI3K? inhibitor), but inhibited by TGX-221 (PI3K? inhibitor) or AS-252424 (PI3K? inhibitor). Simazine did not influence the anti-contractile effect of perivascular adipose tissue. Conclusion: Our data indicate that relaxin-2 produces endothelium- and NO-dependent relaxation of mouse mesenteric arteries by activation of RXFP1 coupled to G_i2-PI3K-eNOS pathway. Targeting vasodilatory G_i-protein-coupled RXFP1 pathways may provide promising opportunities for drug discovery in endothelial dysfunction and cardiometabolic disease.

SUBMITTER: Lian X

PROVIDER: S-EPMC6131674 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a Gαi2-Protein/PI3Kß/γ/Nitric Oxide-Coupled Pathway.

Lian Xiaoming X Beer-Hammer Sandra S König Gabriele M GM Kostenis Evi E Nürnberg Bernd B Gollasch Maik M

Frontiers in physiology 20180904

Background: Relaxins are small peptide hormones, which are novel candidate molecules that play important roles in cardiometablic syndrome. Relaxins are structurally related to the insulin hormone superfamily, which provide vasodilatory effects by activation of G-protein-coupled relaxin receptors (RXFPs) and stimulation of endogenous nitric oxide (NO) generation. Recently, relaxin could be demonstrated to activate Gi proteins and phosphoinositide 3-kinase (PI3K) pathways in cult ...[more]

PMID: 30233409

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Project description:ObjectivesTypically, obesity results from an inappropriate balance between energy uptake from nutrient consumption and burning of calories, which leads to a pathological increase in fat mass. Obesity is a major cause of insulin resistance and diabetes. Inhibitory G proteins (Gαi) form a subfamily that is involved in the regulation of adipose tissue function. Among the three Gαi members, i.e. Gαi1, Gαi2, Gαi3, the Gαi2, protein is predominantly expressed in adipose tissue. However, the functions of the Gαi2 isoform in adipose tissue and its impact on the development of obesity are poorly understood.MethodsBy using AdipoqCreERT2 mice, we generated adipocyte-specific Gnai2-deficient mice to study Gαi2 function, specifically in white and brown adipocytes. These mice were fed either a control diet (CD) or a high fat diet (HFD). Mice were examined for obesity development, insulin resistance and glucose intolerance. We examined adipocyte morphology and the development of inflammation in the white adipose tissue. Finally, intracellular cAMP levels as an indicator of Gαi signaling and glycerol release as an indicator of lipolysis rates were measured to verify the impact of Gαi2 on the signaling pathway in brown and white adipocytes.ResultsAn adipocyte-specific deficiency of Gαi2 significantly reduced diet-induced obesity, leading to decreased fat masses, smaller adipocytes and decreased inflammation in the white adipose tissue relative to littermate controls. Concurrently, oxygen consumption of brown adipocytes and in vivo measured energy expenditure were significantly enhanced. In addition, glucose tolerance and insulin sensitivity of HFD-fed adipocyte-specific Gnai2-deficient mice were improved compared to the respective controls. In the absence of Gαi2, adrenergic stimulation of intracellular adipocyte cAMP levels was increased, which correlated with increased lipolysis and energy expenditure.ConclusionWe conclude that adipocyte Gαi2 is a major regulator of adipocyte lipid content in diet-induced obesity by inhibiting adipocyte lipolysis in a cAMP-dependent manner resulting in increased energy expenditure.

Dataset Information

RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a G?_i2-Protein/PI3Kß/?/Nitric Oxide-Coupled Pathway.

Publications

RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice <i>via</i> a Gα<sub>i2</sub>-Protein/PI3Kß/γ/Nitric Oxide-Coupled Pathway.

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Dataset Information

RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a G?i2-Protein/PI3Kß/?/Nitric Oxide-Coupled Pathway.

Publications

RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice <i>via</i> a Gα<sub>i2</sub>-Protein/PI3Kß/γ/Nitric Oxide-Coupled Pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a G?_i2-Protein/PI3Kß/?/Nitric Oxide-Coupled Pathway.