Horm Mol Biol Clin Invest 2014; 19(2): 89–101

Sarah Elisabeth Louise Even, Maria Gabriela Dulak-Lis, Rhian M. Touyz and Aurelie Nguyen Dinh Cat*

Crosstalk between adipose tissue and blood vessels in cardiometabolic syndrome: implication of steroid hormone receptors (MR/GR) Abstract: Crosstalk between adipose tissue and blood vessels is vital to vascular homeostasis and is disturbed in cardiovascular and metabolic diseases such as hypertension, diabetes and obesity. Cardiometabolic syndrome (CMS) refers to the clustering of obesity-related metabolic disorders such as insulin resistance, glucose and lipid profile alterations, hypertension and cardiovascular diseases. Mechanisms underlying these associations remain unclear. Adipose tissue associated with the vasculature [known as perivascular adipose tissue (PVAT)] has been shown to produce myriads of adipose tissue-derived substances called adipokines, including hormones, cytokines and reactive oxygen species (ROS), which actively participate in the regulation of vascular function and local inflammation by endocrine and/or paracrine mechanisms. As a result, the signaling from PVAT to the vasculature is emerging as a potential therapeutic target for obesity and diabetes-related vascular dysfunction. Accumulating evidence supports a shift in our understanding of the crucial role of elevated plasma levels of aldosterone in obesity, promoting insulin resistance and hypertension. In obesity, aldosterone/mineralocorticoid receptor (MR) signaling induces an abnormal secretion of adipokines, ROS production and systemic inflammation, which in turn contribute to impaired insulin signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular abnormalities. Thus, aldosterone excess exerts detrimental metabolic and vascular effects that participate to the development of the CMS and its associated cardiovascular abnormalities. In this review, we focus on the physiopathological roles of corticosteroid receptors in the interplay between PVAT and the

*Corresponding author: Aurelie Nguyen Dinh Cat, PhD, BHF Glasgow, Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK, Phone: +44 141-3308015, Fax: +44 141-330-3360, E-mail: [email protected] Sarah Elisabeth Louise Even, Maria Gabriela Dulak-Lis, Rhian M. Touyz and Aurelie Nguyen Dinh Cat: Cardiovascular Research and Medical Sciences Institute, University of Glasgow, Glasgow, UK

vasculature, which underlies their potential as key regulators of vascular function. Keywords: cardiometabolic syndrome; corticosteroid receptors; perivascular adipocytes; vascular function. DOI 10.1515/hmbci-2014-0013 Received March 20, 2014; accepted August 6, 2014

Introduction The hallmark of obesity is excessive accumulation of adipose tissue (or adiposity). At the vascular level, adipose tissue is intimately associated with structural and functional characteristics of the vasculature. Individuals with adiposity are characterized as being overweight (BMI 25–30) or obese (BMI  > 30). Obesity and obesity-associated cardiovascular (CV) risk factors have reached epidemic proportions worldwide. Obesity, hypertension and diabetes constitute the ‘cardiometabolic syndrome’ [1, 2]. It is crucial to understand the reciprocal communication between adipose tissue and vasculature to define new mechanisms and strategies for therapeutics. In addition of its classical role as a major storage organ for triglycerides, adipose tissue is a highly dynamic endocrine organ and an important metabolic sensor, producing a large number of bioactive substances [hormones, cytokines, reactive oxygen species (ROS)], collectively termed ‘adipokines’ [3–7], that control systemic insulin sensitivity, immune responses and vascular homeostasis [8]. Adipose tissue is predominantly located around blood vessels (perivascular), around internal organs (visceral) or subcutaneously. Histologically, there are two fundamentally different types of adipose tissue: white (WAT) and brown (BAT) adipose tissues. Their differing anatomic distribution, functions, and mechanisms of regulation has been extensively reviewed [9–12] and will not be further discussed here. A positive correlation between serum aldosterone levels and fat mass has been reported [13–16]. The strict

90      Even et al.: Steroid receptors in adipose-vascular crosstalk relationship linking aldosterone to adipose tissue has been underlined by several clinical and experimental studies. Aldosterone mediates deleterious effects in adipose tissue through genomic and non-genomic pathways, leading to alterations of not only glucose metabolism and insulin sensitivity [17], but also endothelial dysfunction, inflammation, oxidative stress [18]. This is further complicated by the interplay between cortisol and aldosterone and their respective receptors. It is well known that glucocorticoid (GR) and mineralocorticoid (MR) receptors display very close structural and functional homologies. This review will focus on the regulation of vascular function, in particular vasoreactivity, by PVAT through the adipose-vascular axis, and its relevance to CMS-related cardiovascular complications. It will also summarize the role of corticosteroid receptors in mediating the crosstalk between adipose tissue and the vasculature, and highlight their contribution in CMS-associated vascular dysfunction. Finally, the potential use of MR/GR antagonists to prevent and/or attenuate vascular disorders in CMS will be addressed.

cellular structures such as (pre)adipocytes, fibroblasts, endothelial and smooth muscle cells, mesenchymal cells, and immune cells (macrophages, T lymphocytes) and tissue structures (small blood vessels, connective tissue and nerves) (Figure 1) [7]. Perivascular adipocytes are not separated from the blood vessel wall by an anatomic barrier and actually encroach into the outer adventitial region [19, 20]. Hence, PVAT is intimately associated with the CV system and exerts its influence on vascular function including endothelium-dependent vasodilation, inflammation and remodeling, by secreting a large number of bioactive substances, called adipokines (such as hormones, cytokines, peptides, ROS) [21]. In CMS, abnormal secretion of these ‘vasocrines’ occurs, leading to adipocyte dysfunction but also to the development of CV complications associated with the diseases, including obesity, diabetes mellitus and hypertension. This review will focus on whether PVAT influences vasoreactivity in CMS.

Anti-contractile effect of PVAT

Perivascular adipose tissue: characteristics and functional properties Characteristics of perivascular adipocytes Perivascular adipose tissue (PVAT) is present around most blood vessels. It consists of a heterogeneous mixture of

The first studies demonstrating that PVAT is biologically active focused on modulation of vascular reactivity. Indeed, PVAT possesses anti-contractile properties under physiological conditions. Soltis and Cassis were among the first to demonstrate in vitro that PVAT significantly attenuates the contractile responses to noradrenaline of aortic ring preparations from rats [22], which was later confirmed by Löhn and collaborators [23]. Moreover,

Adipocytes Blood vessels Macrophages Fibroblasts Nerves Lymphocytes Endothelial cells Smooth muscle cells Mesenchymal cells Perivascular adipose tissue

Figure 1 Crosstalk between perivascular adipose tissue and the vasculature. Perivascular adipose tissue is composed by adipocytes, fibroblasts, endothelial and smooth muscle cells, mesenchymal and immune cells (macrophages and lymphocytes). PVAT is an active endocrine organ of multiple mediators known as adipokines, including cytokines, hormones, and other factors. TNFα, tumor necrosis factor alpha; IL-6, interleukine-6; ADRF, adventitia-derived relaxing factor; Ang II, angiotensin II; ROS, reactive oxygen species.

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Verlohren and coworkers showed a positive correlation between the vasorelaxing influence and the amount of PVAT [24]. This anti-contractile action is induced by a perivascular adipocyte-derived relaxing factor (ADRF), in analogy to endothelium-derived relaxing factor. The inhibitory action of ADRF is mediated by tyrosine kinase pathways and opening of ATP-dependent K+ (KATP) channels in aorta, whereas in rat mesenteric arteries it involves voltage-dependent K+ channels (Kv). Thus, there are vascular regional differences in the effects of PVAT, possibly as a result of the existence of different ADRFs. In a second work, the same group characterized that the mechanism of ADRF released from rat aortic periadventitial tissue was dependent on Ca2+ and cAMP [25]. Nevertheless, other mechanisms by which PVAT permits this beneficial reduction in vascular contractility may involve the increase in nitric oxide (NO) bioavailability, induced in part by fat-derived adiponectin and endothelium-independent pathways involving hydrogen peroxide (H2O2) generation [26, 27].

Loss of the anti-contractile effect of PVAT in obesity: mechanisms The anti-contractile effect of PVAT is directly dependent of its amount [24]. However in obesity, even if the amount of PVAT is increased, this is not accompanied by an increase in the anti-contractile effect. The anti-contractile potency of ‘healthy PVAT’ is actually lost in obese patients. It is known that obesity triggers both structural and functional changes in PVAT leading to alterations of its paracrine effects on vascular function [27]. Several mechanisms can explain the loss of anti-contractile properties of PVAT in obesity such as adipocytes hypertrophy with resultant hypoxia, inflammation and oxidative stress [27], adipokines dysregulation with an imbalance in the production of PVAT-derived detrimental (leptin, resistin, TNF-alpha, IL-6) and protective (adiponectin, apelin) factors in favor of vasoconstrictor and pro-inflammatory substances, decrease in NO bioavailability, elevated PVAT-derived ROS production such as superoxide anion and hydrogen peroxide, leading to vascular dysfunction. Several signaling pathways have been implicated, such as activation of tyrosine kinase, MAP kinases, NFκB and Rho kinase increase in NADPH oxidase activity, down-regulation of AMPK and eNOS phosphorylations/upregulation of the mammalian target of rapamycin mTOR, and decrease in insulin signaling, leading to insulin resistance, endothelial dysfunction, vascular contractility [28–31] (Figure 2).

These data support the hypothesis of a major paracrine role of PVAT in the regulation of vascular function, which implies the interaction or signaling mechanisms between PVAT and adjacent vessels when PVAT transits from a healthy to a diseased state [32]. In addition to ADRF, there are other PVAT-derived candidates that might modulate vascular function, such as pro- and anti-inflammatory adipokines, the adipose renin-angiotensin-aldosterone system (RAAS) or ROS.

Influence of substances released by PVAT on vascular function Whether PVAT communicates directly with surrounding vasculature has not been well-established. Mediators released by PVAT diffuse across the vascular wall to interact with vascular cells in a paracrine manner.

Adipokines Adipokines are key components of the ‘adipose-vascular axis’ that mediate the interactions between PVAT and adjacent vasculature. Amongst the many adipokines released from adipocytes are hormones, cytokines, chemokines, growth factors and other peptides. A growing body of literature has investigated the paracrine function of PVAT-derived adipokines on vascular function including vasoreactivity, proliferation and migration of vascular smooth muscle cells (VSMCs) and inflammation. Two reviews from Maenhaut [33] and Szasz [34] summarize adipokine-derived paracrine effects in physiological and pathological conditions such as in CMS and CMS-associated cardiovascular disorders. Figure 3, adapted from these reviews, focuses on published studies demonstrating vasorelaxing and/ or vasoconstricting effects of several adipokines (ADRF, adiponectin, angiotensin II, apelin, chemerin, IL-6, leptin, omentin, resistin, ROS, TNF-alpha, visfatin). In addition, a number of studies have reported that adipokines can regulate each other expression and secretion hence modulating cellular processes (vascular cells but also immune cells functions) [6, 21]. In this review, we will focus on studies that involve corticosteroid receptors in the regulation of these adipokines and discuss whether aldo/glucocorticoids and MR/GR may play an important role in the interaction between PVAT and the vasculature by inducing adipokines changes in CMS.

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Blood vessels

MAPKs activation

↑ Rho kinase signaling

Tyrosine kinases

↓ Insulin signaling

↓ NO bioavailability

Vascular dysfunction

Obese PVAT

↑ NFκB activation

↓ AMPK signaling ↑ Rho kinase signaling

Infiltration of inflammatory cells (macrophages)

↓ Insulin signaling

↑ NADPH oxidase activity

Adipokines dysregulation Adipocytes hypertrophy

↑ Cytokines

Inflammation

↑ mTOR signaling

↓ adiponectin ↓ apelin

Hypoxia

↑ ROS

↑ leptin, resistn, ↑ ADCF ↑TNF-α, IL-6

Insulin resistance

Oxidative stress

Figure 2 Mechanisms involved in the loss of anti-contractile properties of PVAT in obesity. This scheme summarizes the major molecular mechanisms involved in the loss of anti-contractile effects of obese PVAT leading to: a) adipocytes hypertrophy, b) adipokines dysregulation, c) excess of ROS production by PVAT, d) macrophages infiltration, resulting in adipose tissue inflammation, hypoxia, insulin resistance, oxidative stress and alterations of vascular functions. ADCF, adipocyte-derived contracting factor; AMPK, AMP-activated protein kinase; IL-6, interleukin-6; MAPKs, mitogen-activated protein kinases; mTOR, mammalian targets of rapamycin; NFkB, nuclear factor kappa B; NO, nitric oxide; PVAT, perivascular adipose tissue; ROS, reactive oxygen species; TNFα, tumor necrosis factor alpha.

Physiologically, PVAT releases adipokines, which increases vasorelaxation. However, in CMS, adipokines expression and secretion is altered: as pro-inflammatory adipokines are increased while anti-inflammatory adipokines expression are diminished, resulting in the development of a chronic, low-grade inflammatory state. This adipokine imbalance is a key event that may promote both systemic metabolic dysfunction and cardiovascular diseases. The increasing numbers of identified adipokines and their impact on vasoreactivity has to be defined. By identifying novel adipokines and their functions, which contribute to the pathogenesis of vascular diseases in obesity and diabetes, it will deepen our understanding of the endocrine and paracrine roles of PVAT in the regulation of vascular function.

Reactive oxygen species While most ex vivo studies indicate that PVAT produces vasorelaxing factors, others have reported the production of an adipocyte-derived contractile factor (ADCF)

that inhibits NO bioactivity [46, 73]. This PVAT-derived contractile property has been suggested to be mediated by ROS and was blocked by inhibitors of NADPH oxidase. ROS are a class of oxygen-derived molecules including superoxide anion (O2.-) and hydrogen peroxide (H2O2), both modulators of vascular tone and released from PVAT. Increased metabolism in obesity results in oxidative stress which is an imbalance between oxidants and antioxidants, in favor of the oxidants thus contributing to metabolic syndrome [74–76]. Isolated arteries from high-fat diet-induced obese mice present endothelial dysfunction shown by a decreased endothelium-dependent relaxation to acetylcholine [77–79]. The impaired endothelium-dependent vasorelaxation was restored by removal of PVAT and by quenching or scavenging ROS, indicating that PVAT-derived ROS is implicated in endothelial function damage. Thus, obese PVAT-derived ROS can have a paracrine action on the vascular wall and impair the endothelium-dependent relaxation [8]. In addition, obesity can impair the vascular antioxidant capacity. Kobayasi et al. demonstrated that obesity-induced endothelial dysfunction is associated with decreased Cu/Zn-SOD protein expression

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ADRF 23,24,26,35

ROS (O2.-, H2O2)26,45-50

Ang II65,66

Adiponectin36-38

Leptin 51-55

Resistin67,68

Omentin 39,40

TNF-alpha 56,57

Chemerin69-72

Visfatin41-44

IL-6 58,59 Apelin 41,60-64

Vasorelaxation

Vasoconstriction

Figure 3 Vasoactive effects of adipokines. Adipokines are key components of the “adipose-vascular axis” that mediate the interactions between PVAT and adjacent vasculature. Amongst the many adipokines released from adipocytes are hormones, cytokines and chemokines. This figure summarizes adipokine-derived paracrine effects on vasoreactivity. ADRF: vasorelaxation through opening of KATP, Kv or KCa channels. Adiponectin: NO-dependent vasorelaxation mediated by Kv channels. Omentin: EC-dependent and -independent vasorelaxation. Visfatin: NO-dependent vasorelaxation. Ang II: vasoconstriction via binding on AT1 receptors. Resistin: no effect on contractility but has been associated with endothelial dysfunction and coronary artery disease. Chemerin: no effect on contractility but has been associated with endothelial dysfunction and coronary artery disease. Superoxide anion: vasoconstriction through Ca2+ sensitization, impairs relaxation by decreasing NO bioavailability, enhances vasoconstriction to peripheral nerve activation by electrical field stimulation. H2O2: EC-dependent and -independent vasorelaxation mediated by opening KATP, Kv or KCa channels, Ca2+-dependent and independent vasoconstriction. Leptin: vasoconstriction because of sympathetic nervous system activation, EC-dependent and independent vasorelaxation. TNF-alpha: EC-dependent and independent vasorelaxation, triggers ET-1 and Ang II-induced vasoconstriction, impairs EC-dependent vasorelaxation because of decrease in NO or increase in ROS production. IL-6: EC-independent vasorelaxation, reduces vasorelaxing effect of PVAT because of ROS production, impairs endothelial function because of increased ROS and decreased NO production. Apelin: NO-dependent vasorelaxation, EC-dependent vasoconstriction. ADRF, adipocyte-derived relaxing factor; Ang II, angiotensin II; IL-6, interleukin-6; KATP, ATP-sensitive potassium channels; Kv, voltagedependent potassium channels; KCa, calcium-activated potassium channels; PVAT, perivascular adipose tissue; ROS, reactive oxygen species; O2.-, superoxide anion; H2O2, hydrogen peroxide; TNFα, tumor necrosis factor alpha.

and consequently superoxide anion accumulation in the aorta from mice with high-fat-induced obesity [77]. Therefore, the increase in ROS levels induced by NADPH oxidases, together with reduced NO production, represents in part the mechanism underlying endothelial dysfunction in CMS [45, 80, 81]. Other mechanisms by which ROS contribute to endothelial dysfunction include the following. 1. Insulin signaling alteration with deficiency of the phosphoinositide-3 kinase (PI3-K)/Akt pathway [82]. In obese Zucker rats, it has been reported that defective PI3-K/Akt signaling consequently resulted in decreased NO bioavailability [83]. 2. Pro-inflammatory signaling with activation of the transcription factor, nuclear factor kappa B (NFkB), leading to increased transcription and synthesis of pro-inflammatory cytokines/adipokines (IL-6, TNF-α, resistin and MCP-1). NFκB activation in adipocytes may also be a key driver of 11-beta-hydroxysteroid dehydrogenase 1 (HSD1) expression, which boosts corticosteroid activity in adipocytes by promoting reduction of inactive cortisone to active cortisol [84]. 3. Protein kinase C beta (PKC-β) activation leading to a decrease in NO production with an increase in adhesion molecules expression and superoxide anion levels [85–87]. Depending on their levels, the environment, the vessel type and the animal species, ROS could exert vasoconstrictor or vasodilator effects. PVAT-derived superoxide anions alter EC-dependent relaxation by decreasing NO bioavailability and enhance contraction in response to peripheral nerve activation by electrical field stimulation [46, 88]. Whether O2.- can directly, or via conversion to H2O2, induce vasoconstriction through Ca2+ sensitization remains unclear [47] (Figure 4). H2O2 is likely to be the ROS most involved in modulating the vasculature as it is more stable, cell permeable and less reactive than other free radicals. Hydrogen peroxide promotes both vasorelaxation and vasoconstriction [45, 89–91]. It induces vasoconstriction through Ca2+-dependent and -independent mechanisms including activation of mitogen-activated protein kinase (MAPK), PKC and Rho kinase signaling [33, 91, 92]. However H2O2 can also induce vasorelaxation through EC-dependent and -independent mechanisms mediated by opening KCa channel, Kv and KATP channels [91] and soluble guanylyl cyclase activation [26], respectively (Figure 4).

94      Even et al.: Steroid receptors in adipose-vascular crosstalk

ROS

O2-. - Alteration of EC-dependent decreasing NO bioavailability;

relaxation

by

-Vasoconstriction through Ca2+-sensitization; - Enhances vasoconstriction to peripheral nerve activation by electrical field stimulation.

H2O2

- EC-dependent and -independent vasorelaxation mediated by opening KCa, Kv, KATP channels and guanylyl cyclase activation; Ca2+-dependent and -independent vasoconstriction mediated by MAPK, PKC or Rho kinase signaling.

Figure 4 Vasoactive effects of ROS. Perivascular adipose tissue-derived ROS can exert vasorelaxing as well as vasoconstricting effects. EC, endothelial cell; NO, nitric oxide; Ca2+, calcium; KCa, calcium-activated potassium channels; Kv, voltage-gated potassium channels; KATP, ATP-dependent potassium channels; MAPK, mitogen-activated protein kinase; PKC, protein kinase C.

MR and GR activations in the development of CMS: dysregulation of adipokine secretion Aldosterone in CMS: regulation of adipokine secretion and expression Aldosterone (aldo) has been implicated in the pathogenesis of CMS, especially in CV complications associated with CMS, such as arterial remodeling and endothelial dysfunction [93–98]. Although this complex relationship is not well-established, there is some evidence of the following. a) High plasma levels of aldo are positively correlated with fat mass [16] where weight loss decreases aldo levels [15], suggesting that the association between plasma aldo levels on the one hand and obesity and insulin resistance on the other hand may be related to adipocyte biology [99–101]. b) Aldo could impact on insulin resistance, oxidative stress, sodium retention and volume overload, increased sympathetic activity, levels of free fatty acids, or pro-inflammatory cytokines as well as adipokines [18, 102, 103]. Aldo exerts its effects through genomic and nongenomic pathways in a mineralocorticoid receptor (MR)-dependent or independent manner [104]. It is wellestablished that cortisol can act equally through both the MR and the GR [18] and MR possesses the same affinity for aldo and glucocorticoids [105]. Both receptors are present

in adipose tissue [106–108]. Thus, adipose aldosteroneinduced effects on vascular function could be mediated through either receptor. Our group has clearly demonstrated that aldosterone can be secreted by adipocytes, similar to other classical adipokine and this secretion is enhanced by angiotensin II and in obese db/db mice [108]. Thus, PVAT-derived aldosterone, through MR- and GR-dependent mechanisms, impacts on vascular signaling and function in particular, it seems to be implicated in the endothelial dysfunction associated with type 2 diabetes [107, 108].

MR and GR activation in CMS Mechanisms by which adipose aldo/MR activation influences vasoreactivity include adipokine dysregulation, oxidative stress and Rho kinase signaling (unpublished personal data – manuscript in preparation). Clinical trials and animal studies support this hypothesis where aldo/ MR activation could affect vascular function through adipokine regulation as MR blockade has beneficial effects in CMS, by reversing inflammation, oxidative stress, and defective insulin signaling at the cellular-molecular level [109–112]. Guo and coworkers demonstrated that eplerenone, an MR antagonist reduced gene expression of pro-inflammatory adipokines (IL-6, TNFα, MCP-1) and increased expression of adiponectin in adipose tissue from obese type 2 diabetic mice [110]. These effects on adiponectin and adipokine gene expression may represent

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a novel mechanism for the CV protective effects of MR blockade. Interestingly, in obese mice, MR expression is significantly up-regulated in adipose tissue [111]. Clinical data showed that treatment of patients with an MR antagonist improved insulin sensitivity and reduced markers of inflammation [113–115]. However, until now the physiological significance of the MR in mature adipocytes remains poorly explored and little is known about the interplay of MR- and GR-mediated regulation of paracrine functions on the vasculature. Thus, MR blockade represent an increasingly used evidence-based therapy for many forms of CV diseases, including hypertension, obesity and diabetes mellitus. Currently, MR antagonists are not recommended for patients with diabetes and microalbuminuria because of the risks of hyperkalemia. Further clinical trials are needed to determine the safety and long-term cardiovascular and renovascular effects of MR antagonists in individuals with CMS, but increasing evidence suggests that MR antagonists may prove to be important therapeutic agents in reducing clinical complications of CMS. Aldosterone regulates pro- and anti-inflammatory adipokines secretion and expression as evidenced by in vitro studies. In cultured adipocytes, aldosterone stimulates leptin mRNA levels [116], yet patients suffering from primary hyperaldosteronism appear to have low serum levels of leptin [117, 118]. Several studies have demonstrated a clear inverse relationship between plasma levels of aldo and circulating levels of adiponectin. For example, highsalt diet-induced hypertensive rats present a decrease in aldosterone levels, and an increase in plasma adiponectin levels [119]. A similar study in humans showed that high-salt diet given to healthy men suppressed plasma renin activity, plasma Ang II and plasma aldo, which correlated with a significant rise in plasma adiponectin [120, 121]. It has now been well-established that low levels of adiponectin is strongly associated with endothelial dysfunction occurring in CMS [122–125]. Furthermore, the effects of aldosterone on adiponectin and PAI-1 expression appear to be mediated through GR but not MR [126]. A recent study has also shown a direct interaction between aldo and apelin in adipocytes through GR-dependent mechanisms [127]. Similar to the inverse relationship between aldo and adiponectin, high plasma levels of aldo are associated with low plasma levels of apelin. Aldosterone increases ROS production by the mitochondria and modulation of NADPH oxidases and thus promotes cardiovascular injury [128, 129]. Aldosterone impairs endothelium relaxation via a redox serine kinase associated with NADPH oxidases and mitochondrial generation of ROS leading to a decrease in NO bioavailability and thus, impairing vasorelaxation [102]. According

to Park et al. [129], aldosterone induces NADPH oxidases activity and increases p22phox, gp91phox and p47phox expressions, which are subunits of the NADPH oxidase family members. MR blockade significantly diminishes oxidative stress, insulin resistance and endotheliumdependent relaxation in obese and diabetic mice [102, 111, 130]. These studies highlight the critical role of MR activation in promoting oxidative stress under pathological conditions such as obesity associated with type 2 diabetes, as well as the possible mechanism through which PVATderived aldosterone may regulate vascular tone through ROS production (Figure 5). Obesity and insulin resistance, key components of CMS, are associated with chronic inflammation. This is characterized by an increased production of pro-inflammatory adipokines such as IL-6, MCP-1, TNF-α [131–134]. Mechanisms leading to obesity-related inflammation may imply corticosteroid metabolism in adipose tissue and their interplay in mediating an inflammatory adipokine response, insulin resistance, and CV disorders [135]. In contrast with elevated aldo levels in obese individuals, cortisol plasma concentrations were shown not to be consistently elevated in obese people [136, 137]. Interestingly, clinical observations have highlighted similarities between metabolic disorders in central ALDOSTERONE

MR/GR?

MR

GLUCOCORTICOIDS GR MR/GR?

+

Adiponectin Apelin

TNF-alpha IL-6 MCP-1 PAI-1 ROS (NADPH oxidase)

PRO-INFLAMMATORY PHENOTYPE

+ Leptin

OXIDATIVE STRESS

VASCULAR TONE DYSFUNCTION

Figure 5 Implication of corticosteroid receptors in adipokines dysregulation in cardiometabolic syndrome. Cardiometabolic syndrome (CMS) is associated with high levels of aldosterone whereas cortisol/corticosterone levels are unchanged. In CMS, MR is overactivated and induced pro-inflammatory adipokines secretion by PVAT and reactive oxygen species (ROS) generation, leading to dysregulation of vascular tone. GR, glucocorticoid receptor; IL-6, interleukin-6; MCP-1, monocytes chemoattracting protein-1; MR, mineralocorticoid receptor; PAI-1, platelet activator inhibitor-1; ROS, reactive oxygen species; TNFα, tumor necrosis factor alpha.

96      Even et al.: Steroid receptors in adipose-vascular crosstalk obesity (visceral adiposity, hyperlipidaemia and insulin resistance) and excess glucocorticoids (GCs) such as in Cushing’s syndrome which strongly suggest that abnormalities in GCs metabolism and action in adipose tissue may be important in the pathogenesis of obesity [138– 140]. Elevated GCs have been demonstrated to play a role in the control of appetite, in impaired adipogenesis, insulin signaling and inducing lipid accumulation resulting in visceral obesity and type 2 diabetes. Transgenic overexpression of 11 beta-HSD-1 (enzyme that regenerates active GCs), in adipose tissue reproduces a metabolic syndrome in mice with central obesity, insulin resistance, dyslipidaemia and hypertension [141, 142], whereas 11 beta-HSD-1 deficiency or inactivation of glucocorticoid action in adipose tissue has beneficial metabolic effects by increasing insulin sensitivity in these mice and by protecting them against obesity and diet-induced metabolic disease [143, 144]. These data provide in vivo evidence that adipose 11 beta-HSD-1 deficiency beneficially alters adipose tissue distribution and function, and suggests a promising pharmaceutical target for the treatment of CMS. Although glucocorticoid action in adipose tissue has long been considered to be exclusively mediated by GR, it may be possible that its actions could also be mediated by MR, as both receptors are present in adipocytes. Caprio et  al. provided strong evidence confirming the importance of MR and GR activation in adipose tissue in regulating an inflammatory adipokine response with opposing and complementary effects by the GR and MR. Indeed selective GR activation induces an anti-inflammatory effect, whereas GR inactivation as well as selective MR stimulation promotes a pro-inflammatory adipokine profile in mature adipocytes [106]. These data suggest the implication of MR in corticosteroid-induced adipogenesis and support the fact that in obesity the disrupted balance between GR and MR activation in adipocytes leads to a decrease in anti-inflammatory adipocyte responses and promotes pro-inflammatory adipocyte responses. Hence, the determination of this imbalance is critical to find out the inflammatory and metabolic adipocyte responses implicated in obesity-associated inflammation and cardiovascular complications [145]. Thus, selective corticosteroid receptor modulation may have therapeutic implications for the prevention and treatment of obesity and insulin resistance.

Outlook There is an increasing interest in the physiopathological role of the corticosteroid receptors in adipose tissue and

the impact on vascular function as MR and GR activation appear to be important contributors to vascular endothelial dysfunction related to cardiometabolic syndrome. A growing body of evidence has already demonstrated that MR antagonism has beneficial effects by reducing inflammation and oxidative stress, leading to improved endothelial function. Future studies will unravel the significance of corticosteroid receptors in the interaction between adipocytes and blood vessels and will elucidate whether this system is involved in the pathogenesis of cardiovascular complications associated with CMS. Further studies are needed to elucidate the molecular mechanisms that regulate the crosstalk between adipose tissue and the vasculature and the role of gluco- and mineralo-corticoids, so that new targets reduce CV disorders associated with CMS can be developed.

Highlights PVAT plays a critical role in modulating vascular tone by releasing numerous vasoactive factors, including adipokines and ROS, that act on endothelial and smooth muscle cells. Findings from in vitro and in vivo studies demonstrate that PVAT is a secondary source of aldosterone, which may promote vascular dysfunction in obesity through MR activation by increasing oxidative stress and decreasing NO bioavailability, while GR activation is not involved. In obesity and type 2 diabetes, adipocyte dysfunction and local inflammation result in impaired production of protective factors (ADRF, adiponectin, apelin) with elevated release of detrimental adipokines (leptin, resistin, IL-6, TNF-α, ADCF) and ROS. Thereby, leading to endothelial dysfunction, insulin resistance and increased contractility associated with cardiovascular disorders related to CMS, such as hypertension, obesity and diabetes mellitus [146]. The regulation of this inflammatory adipokine response may involve GR activation, but not MR activation. Thus, there is an imbalance between the beneficial and detrimental role of PVAT in regulating vascular tone that may be due to the balance between MR and GR activations in adipocytes. In addition, it has been suggested that insulin resistance is linked to mitochondrial dysfunction indicating that the imbalance between oxidants and antioxidants released by PVAT plays a central role in CMS. Thus, studies investigating the interactions between PVAT and blood vessels are important for our understanding of the pathogenesis of CMS and CV complications associated with CMS. This crosstalk is likely to occur on multiple levels:

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1. While some functions of PVAT may contribute to vascular homeostasis, PVAT primarily plays a pivotal role in vascular disorders associated with CMS. 2. On the other hand, the endothelium is also releasing factors such as endothelin-1 or NO that can target the adipose tissue and modulate adipokines production [147, 148]. 3. In addition, inflammatory cells or adipose-derived stem cells might traffic from PVAT into the vessel wall and could trigger inflammation or vascular repair mechanisms. Further studies are needed to explore and test these hypotheses. Acknowledgments: Work from the author’s laboratory was supported by grants from the Canadian Institutes of Health Research (CIHR) and grants from the British Heart Foundation (BHF). RMT is supported through a BHF Chair.

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