Chemerin promotes the proliferation and migration of vascular smooth muscle and increases mouse blood pressure

Kunimoto, Hidemizu; Kazama, Kyosuke; Takai, Mizuho; Oda, Mayuko; Okada, Muneyoshi; Yamawaki, Hideyuki

doi:10.1152/ajpheart.00820.2014

Cited by 64 publications

(62 citation statements)

References 43 publications

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“…Erk MAPK and PLC are not involved in chemerin-dependent calcium flux and contraction. With a host of literature describing the possibility of chemerin’s involvement in hypertension [3– 9], further research is needed to connect this knowledge with an actual treatment. This specific pathway helps to characterize a once unknown mechanism by which chemerin may contribute to obesity-related hypertension.…”

Section: Discussionmentioning

confidence: 99%

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Chemerin-induced arterial contraction is Gi- and calcium-dependent

Ferland

Darios

Neubig

et al. 2017

Vascular Pharmacology

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Chemerin is an adipokine associated with increased blood pressure, and may link obesity with hypertension. We tested the hypothesis that chemerin-induced contraction of the vasculature occurs via calcium flux in smooth muscle cells. Isometric contraction of rat aortic rings was performed in parallel with calcium kinetics of rat aortic smooth muscle cells to assess the possible signaling pathway. Chemerin-9 (nonapeptide of the chemerin S157 isoform) caused a concentration-dependent contraction of isolated aorta (EC50 100 nM) and elicited a concentration-dependent intracellular calcium response (EC50 10 nM). Pertussis toxin (Gi inhibitor), verapamil (L-type Ca2+ channel inhibitor), PP1 (Src inhibitor), and Y27632 (Rho kinase inhibitor) reduced both calcium influx and isometric contraction to chemerin-9 but PD098059 (Erk MAPK inhibitor) and U73122 (PLC inhibitor) had little to no effect on either measure of chemerin signaling. Although our primary aim was to examine chemerin signaling, we also highlight differences in the mechanisms of chemerin-9 and recombinant chemerin S157. These data support a chemerin-induced contractile mechanism in vascular smooth muscle that functions through Gi proteins to activate L-type Ca2+ channels, Src, and Rho kinase. There is mounting evidence linking chemerin to hypertension and this mechanism brings us closer to targeting chemerin as a form of therapy.

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Section: Discussionmentioning

confidence: 99%

“…Loss of white adipose tissue through exercise or bariatric surgery reverses the levels of circulating chemerin [7]. Additionally, the active form of chemerin (chemerin S 157 ) is positively associated with blood pressure in both humans [8] and mice [9]. …”

Section: Introductionmentioning

confidence: 99%

Chemerin-induced arterial contraction is Gi- and calcium-dependent

Ferland

Darios

Neubig

et al. 2017

Vascular Pharmacology

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“…Kaur et al (17) identified ChemR23 in human endothelial cells, and Kostopoulos et al (19) confirmed chemerin and ChemR23 expression in human arteries and PVAT. More recently, infusion of chemerin into the mouse modestly elevated blood pressure (20), and chemerin has been suggested to reduce nitric oxide signaling in the rat aorta (29). Understanding the functions of chemerin is important, because circulating levels of chemerin can be reduced and health can be improved through a number of interventions that include bariatric surgery and exercise (7,22,24,28,30,34,39,44).…”

Section: Discussionmentioning

confidence: 99%

The adipokine chemerin amplifies electrical field-stimulated contraction in the isolated rat superior mesenteric artery

Darios

Winner

Charvat

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Darios ES, Winner BM, Charvat T, Krasinksi A, Punna S, Watts SW. The adipokine chemerin amplifies electrical field-stimulated contraction in the isolated rat superior mesenteric artery. Am J Physiol Heart Circ Physiol 311: H498 -H507, 2016. First published July 1, 2016; doi:10.1152/ajpheart.00998.2015.-The adipokine chemerin causes arterial contraction and is implicated in blood pressure regulation, especially in obese subjects with elevated levels of circulating chemerin. Because chemerin is expressed in the perivascular adipose tissue (PVAT) that surrounds the sympathetic innervation of the blood vessel, we tested the hypothesis that chemerin (endogenous and exogenous) amplifies the sympathetic nervous system in mediating electrical field-stimulated (EFS) contraction. The superior mesenteric artery, with or without PVAT and with endothelium and sympathetic nerve intact, was mounted into isolated tissue baths and used for isometric contraction and stimulation. Immunohistochemistry validated a robust expression of chemerin in the PVAT surrounding the superior mesenteric artery. EFS (0.3-20 Hz) caused a frequency-dependent contraction in isolated arteries that was reduced by the chemerin receptor ChemR23 antagonist CCX832 alone (100 nM; with, but not without, PVAT), but not by the inactive congener CCX826 (100 nM). Exogenous chemerin-9 (1 M)-amplified EFSinduced contraction in arteries (with and without PVAT) was blocked by CCX832 and the ␣-adrenergic receptor antagonist prazosin. CCX832 did not directly inhibit, nor did chemerin directly amplify, norepinephrine-induced contraction. Whole mount immunohistochemical experiments support colocalization of ChemR23 with the sympathetic nerve marker tyrosine hydroxylase in superior mesenteric PVAT and, to a lesser extent, in arteries and veins. These studies support the idea that exogenous chemerin modifies sympathetic nervemediated contraction through ChemR23 and that ChemR23 may be endogenously activated. This is significant because of the wellappreciated role of the sympathetic nervous system in blood pressure control. BECAUSE OF ITS LOCATION, the perivascular adipose tissue (PVAT) has the potential to affect the function of the blood vessels it encases. This can occur by secretion of adipokines that directly affect vascular tone, such as the relaxant adiponectin (25). We recently discovered the protein chemerin in PVAT and demonstrated that a shorter chemerin agonist, chemerin-9, caused direct arterial contraction through activation of the best-characterized chemerin receptor, ChemR23 (3,8,27,33,38,48). Chemerin is secreted from the liver and fat depots (10), functioning as an adipokine that regulates adipogenesis (12,31,32) and as an activator of inflammatory cells (13,50,52). Circulating levels of chemerin are positively associated with body mass index (1,4,9,16,36,37,40). Because of our long-term interest in understanding whether chemerin could play a role in obesity-associated hypertension, we turned our attention to a means by which arterial function could be m...

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“…Most recently, the effect of chemerin as a growth factor in vascular biology was investigated. It was reported that chemerin significantly induced rat arterial smooth muscle cells proliferation as well as migration and increased systolic blood pressure [26]. It was also reported that elevated circulatory and local (periaortic and epicardial adipose tissue) chemerin levels significantly increased and positively correlated with the severity of coronary artery disease [12, 27–29].…”

Section: Discussionmentioning

confidence: 99%

Chemerin Stimulates Vascular Smooth Muscle Cell Proliferation and Carotid Neointimal Hyperplasia by Activating Mitogen-Activated Protein Kinase Signaling

Xiong

Luo

et al. 2016

PLoS ONE

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Vascular neointimal hyperplasia and remodeling arising from local inflammation are characteristic pathogeneses of proliferative cardiovascular diseases, such as atherosclerosis and post angioplasty restenosis. The molecular mechanisms behind these pathological processes have not been fully determined. The adipokine chemerin is associated with obesity, metabolism, and control of inflammation. Recently, chemerin has gained increased attention as it was found to play a critical role in the development of cardiovascular diseases. In this study, we investigated the effects of chemerin on the regulation of vascular smooth muscle cells and carotid neointimal formation after angioplasty. We found that circulating chemerin levels increased after carotid balloon injury, and that knockdown of chemerin significantly inhibited the proliferative aspects of vascular smooth muscle cells induced by platelet-derived growth factor-BB and pro-inflammatory chemokines in vitro as well as prohibited carotid neointimal hyperplasia and pro-inflammatory chemokines in vivo after angioplasty. Additionally, inhibition of chemerin down-regulated the expression of several proteins, including phosphorylated p38 mitogen-activated protein kinase, phosphorylated extracellular signal regulated kinase 1/2, nuclear factor-kappa B p65, and proliferation cell nuclear antigen. The novel finding of this study is that chemerin stimulated vascular smooth muscle cells proliferation and carotid intimal hyperplasia through activation of the mitogen-activated protein kinase signaling pathway, which may lead to vascular inflammation and remodeling, and is relevant to proliferative cardiovascular diseases.

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Chemerin promotes the proliferation and migration of vascular smooth muscle and increases mouse blood pressure

Cited by 64 publications

References 43 publications

Chemerin-induced arterial contraction is Gi- and calcium-dependent

Chemerin-induced arterial contraction is Gi- and calcium-dependent

The adipokine chemerin amplifies electrical field-stimulated contraction in the isolated rat superior mesenteric artery

Chemerin Stimulates Vascular Smooth Muscle Cell Proliferation and Carotid Neointimal Hyperplasia by Activating Mitogen-Activated Protein Kinase Signaling

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