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Anticontractile activity of perivascular fat in obese mice and the effect of long-term treatment with melatonin

Agabiti-Rosei, Claudiaa; De Ciuceis, Carolinaa; Rossini, Claudiaa; Porteri, Enzoa; Rodella, Luigi F.b; Withers, Sarah B.c; Heagerty, Anthony M.c; Favero, Gaiab; Agabiti-Rosei, Enricoa; Rizzoni, Damianoa; Rezzani, Ritab

doi: 10.1097/HJH.0000000000000178

Aims: It has been demonstrated previously that inflammation in perivascular adipose tissue (PVAT) may be implicated in vascular dysfunction. The aim of this study was to investigate the functional responses of small mesenteric arteries in a hyperphagic animal model of obesity after chronic treatment with melatonin, an endogenous hormone with antioxidant and vasculoprotective properties.

Methods and results: Ten obese mice (ob/ob) and 10 control lean mice (CLM) were treated with melatonin 100 mg/kg per day in the drinking water for 8 weeks. Mesenteric small resistance arteries were dissected and mounted on a wire myograph and a concentration-response to norepinephrine was evaluated in vessels with intact PVAT and after PVAT was removed and in the presence of iberiotoxin, a selective blocker of BKCA channels as well as under conditions of induced hypoxia in vitro. The presence of PVAT reduced the contractile response to norepinephrine in both ob/ob and CLM; however, the effect was significantly reduced in ob/ob. The anticontractile effect of PVAT completely disappeared with iberiotoxin preincubation. After melatonin treatment, inflammation was significantly ameliorated, and the contractile response in ob/ob and CLM was significantly reduced when PVAT was removed. Anticontractile effect of PVAT that is lost in obesity can be rescued using melatonin. A reduced expression of adiponectin and adiponectin receptor was observed in perivascular fat of ob/ob, whereas significant increase was observed in ob/ob treated with melatonin.

Conclusion: Melatonin seems to exert a protective effect on arteries from both ob/ob and CLM, counteracting the adverse effect of hypoxia and iberiotoxin.

aClinica Medica, Department of Clinical and Experimental Sciences

bDepartment of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy

cFaculty of Medicine and Health Sciences, Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK

Correspondence to Damiano Rizzoni, MD, Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia, c/o 2a Medicina Spedali Civili di Brescia, Piazza Spedali Civili 1, 25100 Brescia, Italy. Tel: +39 030 3905251; fax: +39 030 3384348; e-mail:

Abbreviations: ADIPOR1, adiponectin receptor 1; ANOVA, two-way analysis of variance for repeated measures; CLM, control lean mice; CLM + MEL, control lean mice treated with melatonin from the 5th to 13th weeks of life; ET-1, endothelin-1; HIF-1, hypoxia-sensitive transcription factor; IL-6, interleukin-6; KPSS, high-potassium (60 mmol/l) PSS; ob/ob, obese mice kept untreated and killed at 13 weeks; ob/ob+MEL, obese mice treated with melatonin from the 5th to 13th week of life; PSS, physiological salt solution; PVAT, perivascular adipose tissue; TNF-α, tumor necrosis factor-α

Received 18 December, 2013

Revised 30 January, 2014

Accepted 17 February, 2014

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