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  • Introduction Obesity constitutes a global


    Introduction Obesity constitutes a global healthcare problem and has many adverse effects on the cardiovascular function [1,2]. Recently, the perivascular adipose tissue (PVAT) has emerged as a relevant fat depot for cardiovascular risk and as a potential trigger in vascular dysfunction. Indeed, PVAT known as an endocrine and paracrine organ [3], due to its localization close to the smooth muscle layer of most systemic blood vessels is considered as a regulator of vascular function. PVAT can secrete some relaxing factors, called PVAT-derived relaxing factors (PDRF), that modulate the vasoconstrictive response to adrenergic stress [4], via endothelium-dependent and -independent mechanisms [5,6]. Among PDRF, adiponectin is known to increase eNOS phosphorylation [7] and reduce ROS production [8] in the vascular wall. Interestingly, the anti-contractile effect of PVAT is lost in patients with metabolic disorders [9] and in rodent models of metabolic syndrome [10]. In pathological conditions, PVAT also contributes to increase the production of reactive oxygen species (ROS) in the aortic wall [8]. Alterations of the eNOS [11] and adiponectin-dependent pathways [8] appear to be involved. Among strategies that can influence both the adipose tissue and the cardiovascular system, exercise training is highly recommended in obese patients [12]. Exercise training improves the vascular endothelial function in healthy subjects [13] and in obese patients [14]. This is mainly mediated by the beneficial effects of exercise on eNOS [15]. To the best of our knowledge, despite eNOS is expressed in the PVAT [16] and exercise is known to activate this enzyme in the smad inhibitor [15], the effects of exercise training in obese rats on eNOS specifically expressed in the PVAT have never been challenged. In this study, we determined, using a rat model of obesity, the impact of exercise training on eNOS expressed in the PVAT and its consequences on vascular function.
    Materials and methods
    Discussion PVAT is a key trigger of vascular dysfunction in obese mice [11] and in patients with type 2 diabetes [12]. We reported here that exercise training is able to reduce PVAT mass as it does on other adipose tissue. More interestingly is the impact of exercise training on the functional state of eNOS in the PVAT. Indeed, NO derived from eNOS in the PVAT is a strong candidate for PDRF [16]. The impact of exercise training on the eNOS-NO pathway in the vascular endothelium is mainly dependent of shear stress. In the PVAT, how exercise is able to impact the expression and the functional state of this enzyme is less evident. Several studies have demonstrated a link between β3-adrenoreceptor-mediated signalling and eNOS activation in the adipocytes [24] and more particularly in the PVAT [15]. In the heart, eNOS activation by exercise is dependent of β3-adrenorecepetor stimulation by catecholamines [25]. In addition, exercise training increases the level of β3-adrenoreceptor [25], which contributes to potentiate NO synthesis in response to adrenergic stress. Conversely, obesity or type2 diabetes is known to reduce the level of β3-adrenoreceptor [2,26]. The β3-adrenorecepetors appear then as potential candidates to explain the opposite effect of HFS diet and exercise on eNOS in the PVAT. Further studies will be needed to evaluate this hypothesis and to decipher the underlying mechanisms. Among the candidate for PDRF, adiponectin is also under the spotlight [23]. Indeed, in the adipocytes surrounding the vasculature, eNOS-PKG dependent synthesis of adiponectin is known to activate eNOS in the vascular wall [23] and to modulate ROS production [27]. In our model exercise training increases both eNOS and adiponectin levels in the PVAT, and reduces ROS production in the vascular wall. In addition, the anticontractile effect of PVAT, obvious only in HFS-Ex smad inhibitor aorta in absence of the endothelium, appears to be dependent of eNOS expressed in the PVAT. This suggests that an interaction between eNOS and adiponectin in the PVAT could explain the beneficial effects of exercise on the vascular wall in HFS rats. Our work suggests then that exercise is able to impact eNOS expression and phosphorylation at the level of PVAT. However, the potential role of weight loss cannot be excluded since exercise training in our model of obese rats is associated with reduced body mass (HFS: 720 ± 42 g; HFS-Ex: 585 ± 15 g, p < 0.05) Indeed, it has been previously reported that weight loss in obese rats normalized the level of eNOS in the PVAT [16], that could contribute to the restoration of PVAT anticontractile capacity. Further studies will be needed to decipher how exercise training is able to directly impact eNOS in the PVAT and to identify the signalling pathway involved.