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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2016 Dec 14;174(20):3411–3424. doi: 10.1111/bph.13666

Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets

Ioannis Akoumianakis 1, Akansha Tarun 1, Charalambos Antoniades 1,✉
PMCID: PMC5610156  PMID: 27976387

Abstract

Adipose tissue (AT) is an active endocrine organ with the ability to dynamically secrete a wide range of adipocytokines. Importantly, its secretory profile is altered in various cardiovascular disease states. AT surrounding vessels, or perivascular AT (PVAT), is recognized in particular as an important local regulator of vascular function and dysfunction. Specifically, PVAT has the ability to sense vascular paracrine signals and respond by secreting a variety of vasoactive adipocytokines. Due to the crucial role of PVAT in regulating many aspects of vascular biology, it may constitute a novel therapeutic target for the prevention and treatment of vascular disease pathogenesis. Signalling pathways in PVAT, such as those using adiponectin, H2S, glucagon‐like peptide 1 or pro‐inflammatory cytokines, are among the potential novel pharmacological therapeutic targets of PVAT.

Linked Articles

This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue – Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc

Abbreviations

ACEi

ACE inhibitor

ADRF

adipocyte‐derived relaxing factor

AngII

angiotensin II

ARB

angiotensin receptor blocker

AT

adipose tissue

CAD

coronary artery disease

CBS

cystathionine β‐synthase

CCL2

Chemokine (C‐C motif) ligand 2

CSE

cystathionine γ‐lyase

DPP4

dipeptidyl peptidase 4

EpAT

epicardial adipose tissue

GLP‐1

glucagon‐like peptide 1

MR

mineralocorticoid receptor

MST

3‐mercaptopyruvate sulfurtransferase

PVAT

perivascular adipose tissue

RAAS

renin‐angiotensin‐aldosterone system

TLR4

toll‐like receptor 4

VSMCs

vascular smooth muscle cells

Tables of Links

TARGETS
Enzymes a G protein‐coupled receptors c
ACE, angiotensin converting enzyme Angiotensin receptors
CBS, cystathionine β‐synthase GLP‐1 receptor
CSE, cystathionine γ‐lyase Catalytic receptors d
DPP4, dipeptidyl peptidase 4 TLR4
eNOS, endothelial NOS
MST, 3‐mercaptopyruvate sulfurtransferase
Nuclear hormone receptors b
Mineralocorticoid Receptors
PPARγ
LIGANDS
Adiponectin
Aldosterone
Angiotensin II
GLP‐1
H2O2
H2S
IL‐6
Leptin
CCL2
NADPH
TNF
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These Tables list key protein targets and ligands in this article and are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Southan et al., 2016), and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 (a,b,c,dAlexander et al., 2015a,b,c,d).

Introduction

Increased vascular inflammation and oxidative stress are critical features in atherogenesis. Indeed, it has long been established that atherosclerotic lesions are characterized by the activation of Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, enzymes dedicated to superoxide (O2 .‐) production, as well as by increased uncoupling of endothelial nitric oxide synthase (eNOS) resulting in further increases in vascular O2 .‐ generation (Li et al., 2014). Vascular inflammation is triggered through redox‐sensitive pro‐inflammatory signalling pathways, and can, in turn, stimulate further production of reactive oxygen species (Biswas, 2016). Such stimuli induce the migration of vascular smooth muscle cells (VSMCs), which is an important element of atherosclerotic lesion progression eventually propagating plaque rupture (Bennett et al., 2016). Therefore, the combination of vascular oxidative stress and inflammation creates a vicious cycle that is further supported by a variety of metabolic and genetic risk factors leading to atherogenesis (Libby et al., 2002).

Until recently, adipose tissue (AT) was believed to be a passive reservoir for energy storage along with supportive and thermoregulatory properties. However, during the last decade, it has become clear that AT is a dynamic endocrine organ (Kershaw and Flier, 2004), the quantity and (more importantly) the biological behaviour and anatomical variability of which are involved in the pathogenesis of metabolic syndrome, insulin resistance and cardiovascular disease (Berg and Scherer, 2005; Hajer et al., 2008). Indeed, visceral AT, the AT depot that surrounds most organs, has been revealed as a metabolically active AT depot that is expanded in cases of central obesity and secretes pro‐inflammatory cytokines into the circulation, being consistently linked with the development of systemic insulin resistance and vascular disease (Alexopoulos et al., 2014). On the contrary, lower body adiposity is not related with cardiometabolic disease, whereas some reports even identify a possibly protective role for gluteal AT (Karpe and Pinnick, 2015). Consistent with this finding, subcutaneous AT mass of the gluteal region has been suggested to act as a buffering system for excess nutrient and fat accumulation (Snijder et al., 2005), and is positively correlated with plasma levels of adiponectin, an adipokine with beneficial cardiovascular and metabolic effects (Buemann et al., 2006; Antonopoulos et al., 2011). This regional variability of AT biology highlights its complex role in vascular disease pathogenesis and suggests that it is the quality, the biological function and the regional variability, rather than the quantity of AT that determine its overall effects on the vascular wall.

Perivascular AT (PVAT) consists of fat directly attached to the outer vascular wall. Initially believed to provide structural support to the underlying vessels, PVAT is now recognized as a unique AT depot that actively regulates vascular function, due to its proximity to the vascular wall as well as its ability to produce a wide range of molecules collectively known as adipocytokines, which exert paracrine vascular effects (Rajsheker et al., 2010; Van de Voorde et al., 2014). Recent evidence suggests that the crosstalk between PVAT and the vascular wall is actually bidirectional, allowing for PVAT to act as a sensor of vascular oxidative stress and inflammation and to subsequently respond by altering its secretory behaviour and therefore its paracrine effects on the vascular wall (Margaritis et al., 2013).

In this review, we discuss the biological roles of PVAT in vascular disease, and we focus on its potential as a target for therapeutic intervention.

PVAT: overview of structure and function

PVAT is a layer of AT surrounding the wall of most human vessels, with no clear anatomical barrier between the two (Siegel‐Axel and Haring, 2016). Despite being an important element of the vascular wall, PVAT in total comprises no more than approximately 3% of total body AT mass (Lee et al., 2013). Microscopically, PVAT contains adipocytes as well as stromal cells (mainly fibroblasts and monocytes) and vasa vasorum (Szasz et al., 2013). The composition of PVAT often varies between vascular beds, possibly to accommodate its distinct, tissue‐specific roles (Gil‐Ortega et al., 2015). PVAT volume also differs depending on local regulatory mechanisms, as shown by studies linking the expansion of PVAT around the human coronaries with coronary atherosclerosis (Siegel‐Axel and Haring, 2016).

PVAT often simulates characteristics of brown AT (BAT) (Gu and Xu, 2013), such as the presence of abundant vasculature, along with adipocytes containing many small lipid droplets and ample mitochondria (Saely et al., 2012). This is in contrast with most other AT depots in adults that belong to the white AT (WAT) type, containing lipid‐rich adipocytes with single lipid droplets (Saely et al., 2012). BAT utilizes energy for heat production, in contrast with WAT which predominantly stores energy in the form of fatty acids. BAT may also secrete biologically active molecules (Saely et al., 2012; Wang et al., 2015). The similarity of PVAT to BAT suggests that PVAT may be involved in local energy utilization, while its rich vasculature may facilitate adipogenesis via the local effect of endothelium‐derived growth factors (Gu and Xu, 2013). Furthermore, PVAT apparently loses its BAT‐like properties in obesity and this may play an important role in obesity‐related cardiovascular disease (Gu and Xu, 2013). The biological implications of the similarity between PVAT and BAT require further investigation.

From a functional point of view, the unique anatomy of PVAT distinguishes it from other AT depots in the sense that it allows for its continuous paracrine interaction with the vascular wall that may be independent of systemic factors. A variety of adipocytokines is secreted by PVAT, and is able to exert both paracrine and endocrine roles (Table 1). Such adipocytokines include molecules originating from adipocytes, including adiponectin, leptin and omentin, as well as cytokines mainly coming from inflammatory cells of the stromal component of PVAT, including T lymphocytes and macrophages, such as Tumour necrosis factor (TNF) (Lee et al., 2013). In addition, PVAT expresses a variety of enzymatic systems regulating redox state (Gao et al., 2007) and is thus potentially able to convey local redox‐sensitive signals to the vascular wall. The secretome of PVAT is influenced by metabolic stimuli such as inflammation, obesity and insulin resistance, which affect the differentiation status of adipocytes as well as the degree and polarization of its infiltrating inflammatory cells (Siegel‐Axel and Haring, 2016). The PVAT secretome is also uniquely dependent upon its local interactions with the vascular wall (Gu and Xu, 2013). Consequently, unravelling the potential biological roles of the PVAT secretome in cardiovascular disease is extremely challenging.

Table 1.

Major adipose tissue products and their main biological roles and pharmacological potential in vascular biology

Adipose tissue product Functions Pharmacological targeting
Adiponectin Insulin‐sensitizing, antioxidant and anti‐inflammatory properties PPARγ agonists and ARBs up‐regulate adiponectin expression; novel AdipoR agonists may be useful for stimulation of adiponectin signalling (Iwaki et al., 2003; Nakamura et al., 2009; Okada‐Iwabu et al., 2013)
Leptin Hyperleptinaemia and leptin resistance are associated with cardiometabolic disease, but the direct effects of this hormone in different disease settings are controversial At present there is no efficient targeting option for leptin in the context of cardiovascular disease; commonly used drugs such as ARBs have been shown to increase plasma leptin (Usui et al., 2007)
Omentin Insulin‐sensitizing and antioxidant effects Omentin is an attractive therapeutic target due to its potential beneficial roles; however, no specific treatments have been proposed yet
Resistin Promotion of insulin resistance, inflammation, and oxidative stress Drugs such as statins and ACEi/ARB have been revealed to down‐regulate expression of resistin in AT and reduce its circulating levels (Araki et al., 2006; Hu et al., 2007)
TNF Wide range of pro‐inflammatory effects, induction of oxidative stress and insulin resistance Anti‐TNF treatment is an efficient way of inhibiting TNF, but is associated with significant side effects; several drugs including ACEi and statins have been proposed to suppress TNF expression in some studies (Kortekaas et al., 2014; Fukuda et al., 2015)
IL‐6 Potent pro‐inflammatory properties, induction of oxidative stress Anti‐IL‐6 monoclonal antibodies have been developed as therapeutic modalities; their use in cardiovascular disease however is compromised by their non‐specific side effects
Angiotensinogen/AngII/Aldosterone Pro‐oxidant and pro‐inflammatory roles on the vascular wall ACEi and ARB are established drugs that potently inhibit the AngII/aldosterone axis and its detrimental effects in a variety of cardiovascular diseases (Doulton et al., 2005; Anand et al., 2006; Briones et al., 2012)
H2S Pro‐angiogenic, anti‐atherogenic, antioxidant, vasoactive (predominantly vasodilatory), anti‐inflammatory (primarily), possible O2 sensor Direct targeting of H2S is challenging; H2S donors have had limited usefulness in the treatment of cardiovascular disease thus far. Further exploration of endogenous mechanisms regulating H2S production may reveal novel targets (Beltowski, 2015)
ROS & H2O2 Mostly pro‐oxidant and pro‐inflammatory roles resulting in vasoconstriction and endothelial dysfunction; H2O2 may have novel signal transduction properties The biological roles of adipose tissue‐derived ROS are well established (Gao et al., 2007; Maenhaut and Van de Voorde, 2011). However, no efficient antioxidant treatments exist at present, although a variety of medications may interfere with ROS production
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Apart from their direct, paracrine effects, adipocytokines originating from PVAT may also diffuse into the lumen of the underlying vessels, reaching adjacent vascular segments that are outside their paracrine range. This has been described as a ‘vasocrine’ effect of PVAT, and it highlights its unique ability to locally regulate the homeostasis of individual vascular beds (Yudkin et al., 2005). Such vasocrine signalling may be crucial for the handling of blood glucose and the development of systemic insulin resistance and type 2 diabetes mellitus by regulating perfusion of organs such as skeletal muscle. It also serves as an elegant example of the in vivo crosstalk between metabolic disease and vascular dysfunction (Yudkin et al., 2005).

Epicardial AT (EpAT) is often regarded as a distinct type of PVAT due to its close proximity to the large coronary arterial branches (Ouwens et al., 2010). EpAT is expanded and assumes a pro‐inflammatory phenotype in coronary artery disease (CAD) (Iacobellis, 2015). Given this possible role in the development of CAD, EpAT may be considered a promising therapeutic target in cardiovascular diseases (Payne et al., 2012; Gu and Xu, 2013; Mazurek and Opolski, 2015). Interestingly, while many clinical studies perceive EpAT as one entity, often synonymous with pericoronary AT or the fat surrounding the coronaries (Picard et al., 2014; Aydin et al., 2015), a recent meta‐analysis strongly correlates only EpAT volume at the left atrioventricular groove with CAD (Wu et al., 2014). This suggests that the effects of EpAT may vary depending on its proximity with the coronaries, further implying that pericoronary AT may have properties that differ from the rest of EpAT (non‐pericoronary EpAT). Furthermore, recent work has shown that EpAT can also interact not only with the coronaries but also with the myocardium in a bidirectional paracrine way (Antonopoulos et al., 2016a). Considering that coronary and myocardial function are interrelated, unravelling the spectrum of the interactions between EpAT and both the coronaries and the myocardium, and ultimately its role in the context of cardiovascular disease, is extremely challenging.

The role of PVAT in metabolic and vascular disease

Effects on vascular contractility

It has gradually been recognized that PVAT may be able to influence a variety of physiological biological processes in the vasculature, such as vascular contractility. Indeed, in vitro as well as ex vivo animal studies have revealed the ability of PVAT to influence vascular contractile responses, presumably by secreting an adipocyte‐derived relaxing factor (ADRF) which is able to elicit vasorelaxation (Dubrovska et al., 2004; Zavaritskaya et al., 2013). Although the presence of such a factor is now widely accepted, it is still unclear if ADRF is actually a novel, unidentified factor or a known signalling molecule, or even a combination of molecules, for which this particular vasorelaxant role on the crosstalk between PVAT and the vascular wall has not yet been described.

Adiponectin, nitric oxide (NO), hydrogen sulfide (H2S) and palmitic acid methyl ester (PAME) have all been proposed as being ADRFs (Fernandez‐Alfonso et al., 2013; Siegel‐Axel and Haring, 2016). Evidence suggests that the anti‐contractile effect of ADRF is mediated by the voltage‐gated potassium (Kv) channels of VSMCs, which may identify this channel family as a potential therapeutic target (Tano et al., 2014). This ability of PVAT to regulate vascular tone and endothelial function is abolished in hypertension and obesity (Lu et al., 2011; Oriowo, 2015). The loss of this vasodilatory effect of PVAT in cases of obesity may also be partially due to the secretion of inflammatory cytokines produced by the increased number of infiltrating macrophages (Oriowo, 2015).

Roles in local inflammation and VSMC migration

Evidence suggests that the PVAT secretome is altered in disease states such as obesity and atherosclerosis (Verhagen and Visseren, 2011; Lee et al., 2013). Many studies have demonstrated increased infiltration of PVAT by macrophages in obesity and atherosclerosis in animal models (Szasz et al., 2013) and humans (Henrichot et al., 2005). The expression and secretion of pro‐inflammatory cytokines such as the chemokine Chemokine (C‐C motif) ligand 2 (CCL2) and Interleukin‐6 (IL‐6) in humans is higher in PVAT compared to other AT depots (Chatterjee et al., 2009), implying that PVAT may exert a net pro‐atherogenic effect on the vascular wall, although this concept is highly controversial (Verhagen and Visseren, 2011). PVAT also stimulated proliferation of VSMCs in a rat model (Barandier et al., 2005), and such an effect may be mediated by leptin (Gil‐Ortega et al., 2015). By regulating the proliferation of VSMCs, PVAT is potentially able to regulate vascular angiogenic responses to a variety of stimuli, an effect with pathophysiological implications (Bennett et al., 2016). In addition, PVAT may influence endothelial cell activation and migration of VSMCs, indicating that it may regulate a variety of vascular responses in health and disease (Van de Voorde et al., 2014).

Effects on endothelial function and vascular redox state

A number of mechanistic studies have provided insight into the mechanisms by which PVAT affects vascular redox state and NO bioavailability. Recently, ex vivo studies of relaxation in vascular rings revealed that diet‐induced obesity in mice results in impaired endothelial NO bioavailability through deficiency of the eNOS substrate L‐arginine and eNOS uncoupling (Xia et al., 2016). This difference was solely attributed to PVAT, as isolated vascular segments (after removal of PVAT) did not differ between obese and non‐obese mice (Xia et al., 2016). The relationship of PVAT with NO bioavailability has also been confirmed in pre‐diabetic patients in vivo, where MRI‐assessed PVAT volume was inversely correlated with flow‐mediated dilatation of the brachial artery (Rittig et al., 2008). PVAT may also secrete paracrine factors that reduce NO bioavailability via caveolin‐1 mediated events (Lee et al., 2014).

Obesity has also been associated with reduced phosphorylation of eNOS at its activation site, Ser1177, and has been associated with impaired endothelial function in ex vivo models of animal and human vessels. This latter effect was abolished after separation of the vascular wall from its surrounding PVAT or after incubation with SOD as a means to scavenge O2 .‐ (Greenstein et al., 2009). PVAT has also been shown to produce O2 .‐ and hydrogen peroxide (H2O2), which induce vasoconstriction and vascular oxidative stress (Gao et al., 2007; Lobato et al., 2012; Wang et al., 2014). These findings highlight the importance of oxidative stress from the PVAT, indicating that PVAT in obese subjects may also increase oxidative stress in the underlying vascular wall.

PVAT may also contribute to the development of vascular insulin resistance in the presence of obesity. Indeed, ex vivo insulin‐mediated vasorelaxation was impaired in diabetic mice in the presence of PVAT, compared with vascular segments separated from their PVAT (Meijer et al., 2013). These mice also exhibit an increase in PVAT mass with a change in the secretory profile of PVAT (reduced adiponectin). In addition, inhibition of c‐Jun N‐terminal kinase (JNK) in this fat depot seems to restore endothelial function in vascular segments, suggesting that PVAT may induce vascular insulin resistance via JNK activation (Meijer et al., 2013).

Collectively, these experimental findings suggest that PVAT is a vital regulator of endothelial function, NO bioavailability and vascular redox state. In cases of obesity, in particular, PVAT loses its vasoprotective effects and may contribute to oxidative stress and endothelial dysfunction, as well as local inflammation via the production of pro‐inflammatory adipocytokines (Verhagen and Visseren, 2011; Virdis, 2016). Furthermore, PVAT may influence insulin signalling at the vascular level, thus providing a potential link between systemic and vascular insulin resistance, events that are characteristic of obesity‐related vascular disease.

Clinical aspects of the relationship between PVAT and vascular disease

As mentioned earlier, many clinical studies have linked obesity, especially visceral AT volume, with cardiovascular risk, while also highlighting the significance of the regional variability in AT function. Furthermore, PVAT has been identified as a potentially significant regulator of vascular biology, and such findings have been confirmed in humans by several translational studies (Aghamohammadzadeh et al., 2012). On the other hand, results regarding the overall association of PVAT with cardiovascular risk are rather inconclusive. Indeed, EpAT and pericoronary AT thickness have been associated clinically with coronary calcification and cardiovascular risk factors such as plasma cholesterol and intima‐media thickness (Greif et al., 2009; Sinha et al., 2016). However, most of these associations are driven by the overall visceral AT content, as confirmed by the Framingham Heart study, which revealed that the associations of EpAT and PVAT around the thoracic aorta with cardiovascular disease risk were dependent upon visceral AT, the only independent predictor of cardiovascular risk (Britton et al., 2013). On the other hand, EpAT thickness has been independently associated with coronary calcification, along with atherosclerotic plaque burden and vulnerability (Liu et al., 2010; Park et al., 2013). Interestingly, EpAT volume has also been independently associated with the risk of atrial fibrillation and left atrial volume (Fitzgibbons and Czech, 2014), suggesting that the interaction of EpAT with the myocardium may be clinically more relevant than the one with the coronaries. In light of this, pericoronary AT may prove to be a more sensitive biomarker of CAD, but better imaging tools are required for its accurate characterization.

PVAT as a recipient of vascular signals: novel aspects of the crosstalk between PVAT and the vascular wall

The ability of PVAT to affect vascular biology in a paracrine, outside‐to‐inside manner (from the PVAT to the vascular wall) is now widely accepted. However, recent work from our group has introduced the concept of inside‐to‐outside signals (from the vascular wall to the PVAT), suggesting that the secretory profile of PVAT is largely driven by paracrine signals from the adjacent vessel (Antonopoulos et al., 2015). We have recently found that circulating levels of adiponectin are driven by AT depots remote to the vascular wall (such as subcutaneous AT) and the systemic effects of adiponectin improve vascular redox state and NO bioavailability in patients undergoing coronary artery bypass graft surgery (Margaritis et al., 2013). Conversely, we also found that the expression of adiponectin in PVAT is positively correlated with O2 .‐ production from the underlying vessel (Margaritis et al., 2013). These findings imply that adiponectin expression is differentially regulated in various AT depots, and that local mechanisms may override the effect of systemic factors in the regulation of the secretome of PVAT.

Attempting to explain the positive association between PVAT‐derived adiponectin and O2 .‐ production in the underlying artery, we demonstrated that vascular oxidative stress leads to the release of oxidation products such as 4‐hydroxynonenal from the vascular wall that could diffuse to the surrounding PVAT serving as an inside‐to‐outside messenger able to activate Peroxisome proliferator‐activated receptor gamma (PPARγ) signalling, a well‐known regulator of adiponectin expression, in PVAT (Margaritis et al., 2013). Therefore, apart from the more established outside‐to‐inside signalling, PVAT is also subject to inside‐to‐outside signals with the human vascular wall. This allows PVAT to act as a ‘sensor’ of vascular pathology, thus being able to adjust its own secretome appropriately, as a local defence mechanism against cardiovascular disease. However, this crosstalk may be impaired in conditions such as insulin resistance or diabetes, partly explaining the increased vascular oxidative stress observed in these disease states. As this atheroprotective mechanism has been discovered in atherosclerosis‐free vessels (such as the internal mammary arteries), it is possible it contributes to the well‐established resistance of these arteries to atherosclerosis. It is still unknown whether the same mechanism is also present in PVAT surrounding diseased arteries such as the coronaries.

Prospects and challenges in pharmacological targeting of PVAT

Lifestyle changes have long been proposed as a means of weight loss and concomitant reduction of obesity‐associated disease risk. These include diet, physical activity and behavioural therapy for maintenance of weight control (Wadden et al., 2012). Such measures are easily applicable at a large scale for primary and secondary prevention in cardiovascular disease. Even more importantly, physical activity has been associated with a reduction of inflammation in AT and better cardiovascular function in insulin‐resistant rats (Crissey et al., 2014), and with decreased EpAT thickness in obese humans (Kim et al., 2009).

On the other hand, the long‐term benefit of lifestyle changes on cardiovascular disease progression is controversial (Huerta et al., 2004; Thompson et al., 2012), as moderate obesity has been associated with improved cardiovascular outcomes in secondary prevention, an observation called ‘obesity paradox’ (Antonopoulos et al., 2016b). This reflects the distinction between obesity as a phenotype and AT biology, and reflects a lack of understanding regarding the interactions between AT and the cardiovascular system in humans, highlighting the need for more translational studies which will identify the correct therapeutic targets for the prevention and treatment of vascular disease in obesity. Lifestyle changes such as physical activity, albeit still viable options for treatment of obesity, should be integrated in a broader understanding of AT biology. The new concept that PVAT behaves as a dynamic sensor of vascular biology, modifying its secretory profile accordingly suggests that targeting of individual AT depots would be of more benefit than targeting overall AT mass reduction. It also suggests that if we were able to control the PVAT‐vessel interactions, we may be able to enhance the vasoprotective potential of PVAT, using it against vascular disease pathogenesis.

It is now widely accepted that PVAT, just as any other AT depot, secretes a wide variety of adipocytokines with both beneficial (adiponectin, H2S and omentin) and detrimental (TNF, IL‐6 and resistin) effects on the vasculature (Rajsheker et al., 2010). Even more importantly, the net cardiovascular effect of the PVAT secretome depends upon the underlying disease context (Lee et al., 2013). However, every single one of these adipocytokines has a variety of wide‐reaching systemic effects, making their universal targeting challenging. Also, since there is little consensus in defining those PVAT characteristics with beneficial or detrimental cardiovascular effects under different disease states, targeting PVAT and its secretory profile is quite difficult (Fasshauer and Bluher, 2015). Furthermore, it is unclear whether it would be better to aim at potentiating actions of presumably anti‐atherogenic adipocytokines, such as adiponectin, or inhibit the actions of pro‐atherogenic adipocytokines such as resistin, or both (Andrade‐Oliveira et al., 2015). It is also unclear which cell type within the AT needs to be targeted or which key transcriptional pathways need to be modified to improve its overall secretory profile.

Identifying novel therapeutic targets in PVAT

PPARγ and adiponectin axis

At present, adiponectin is one of the most thoroughly studied adipocytokines. Many publications have identified a plethora of anti‐inflammatory, insulin‐sensitizing and antioxidant roles for adiponectin. Indeed, adiponectin induces phosphorylation‐mediated activation of the AMPK‐activated protein kinase (AMPK), whereas it may be able to inhibit serine phosphorylation of the insulin receptor substrate IRS1, thereby improving insulin sensitivity and overall insulin signalling in a variety of tissues (Ruan and Dong, 2016). In addition, adiponectin has direct antioxidant roles in the human vascular wall (Margaritis et al., 2013; Antonopoulos et al., 2015). Additionally, adiponectin induces M2 macrophage polarization while inhibiting inflammatory infiltration and reducing lipid content in AT (Ruan and Dong, 2016).

Despite these roles, the value of adiponectin as a therapeutic target at a clinical level has not been adequately explored. The half‐life of adiponectin, estimated to be approximately 75 min (Halberg et al., 2009), adds practical complexity to the pharmacological regulation of its circulating levels. A way to bypass direct targeting of adiponectin while still intervening in adiponectin signalling would be to target adiponectin receptors (AdipoR1 and AdipoR2). Recently, an orally administered adiponectin receptor agonist improved insulin sensitivity and glucose tolerance in mice, suggesting that in vivo signalling of adiponectin may be beneficial, but its significance in vascular disease remains to be evaluated (Okada‐Iwabu et al., 2015).

An upstream regulator of adiponectin expression and secretion from AT is PPARγ (Antonopoulos et al., 2014), which facilitates the beneficial effects of this adipocytokine. PPARγ is an important regulator of adipocyte function, with diverse effects on whole body glucose and lipid metabolism. Activation of PPARγ in a variety of tissues such as the liver and skeletal muscle ameliorates insulin resistance (Hevener et al., 2003). Additionally, PPARγ improves insulin sensitivity and prevents lipotoxicity in AT (Lehrke and Lazar, 2005; Medina‐Gomez et al., 2007). Pharmacological PPARγ agonists such as thiazolidinediones have long been used in type 2 diabetes as a means of insulin sensitization. However, despite their lipid‐ and glucose‐lowering effects, these agents have a variety of adverse effects including a reportedly elevated risk for heart failure (Ciudin et al., 2012). This highlights the need for better understanding of the tissue‐specific effects of PPARγ, in order to target its signalling more effectively. The pharmacological regulation of PPARγ/adiponectin signalling is illustrated in Figure 1.

Figure 1.

Figure 1

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Overview of the potential cardiovascular pharmacology of PVAT. PVAT secretes adipocytokines originating from adipocytes (e.g. adiponectin, leptin, omentin, H2S, DPP4 and aldosterone) or from immune cells such as lymphocytes and macrophages (TNF, IL‐6 and other IL). These adipocytokines influence vascular redox state (i.e. the production of reactive oxygen species (ROS), such as O2 .‐, H2O2 and peroxynitrite (ONOO‐)), as well as the migration and proliferation of VSMCs, regulating vascular injury and atherogenesis. Various pharmacological agents influence the secretome of PVAT. PPARγ agonists, statins, ACEi and ARBs as well as mineralocorticoid receptor antagonists and aldosterone antagonists all up‐regulate PPARγ, in contrast with thiazides. PPARγ in turn stimulates adiponectin secretion from adipocytes, which inhibits oxidative stress and restores the bioavailability of tetrahydrobiopterin (BH4), a critical co‐factor of eNOS, resulting in improved eNOS coupling and increased NO bioavailability. Adiponectin expression is also up‐regulated in response to vascular oxidative injury via novel mediators such as 4‐hydroxynonenal (4HNE), a lipid peroxidation product. ACEi, ARB and aldosterone inhibitors as well as MR inhibitors also inhibit the detrimental pro‐oxidant effects of AngII and aldosterone signalling. ROS as well as cytokines produced by immune cells of PVAT are also involved in vascular oxidative injury and pro‐inflammatory signalling, and these effects are inhibited by statins and possibly DPP4 inhibitors. Statins also up‐regulate adipocyte production of H2S, a gas with vasorelaxant and PPARγ‐stimulating roles, possibly via enzymes such as cystathionine γ‐lyase (CSE). Further investigation of local PVAT‐vessel interactions may provide novel therapeutic options for vascular disease.

Endogenous H2S

H2S has recently emerged as an important signalling molecule in the cardiovascular system, endogenously synthesized by enzymes such as cystathionine γ‐lyase (CSE), cystathionine β‐synthase (CBS) and 3‐mercaptopyruvate sulfurtransferase (MST), and is now believed to cross plasma membranes, allowing it to not only have autocrine but also paracrine and endocrine effects (Polhemus and Lefer, 2014; Wallace and Wang, 2015).

In particular, H2S has significant pro‐angiogenic (Papapetropoulos et al., 2009), anti‐atherosclerotic (Xie et al., 2016) and antioxidant (Wallace and Wang, 2015) roles in the vasculature. It has also been shown to have anti‐inflammatory (Zanardo et al., 2006) and vasodilatory effects (Mustafa et al., 2011), but these effects are still controversial with different experimental settings often yielding differing effects (Li et al., 2011; Polhemus and Lefer, 2014). Despite these known and sometimes controversial effects on the vasculature, little is known about H2S's effects on vascular function in humans in vivo. A recent observational study indicated that plasma H2S is elevated in vascular disease in men (Peter et al., 2013), while there is a clinical trial (Phase I) suggesting that H2S may lead to cardiovascular benefits by increasing NO bioavailability in vivo (Polhemus et al., 2015) (NCT01989208; NCT02278276). However, there is no clinical trial to date examining and identifying the effects of H2S on vascular clinical endpoints, though such studies are crucially needed.

H2S is also produced by AT (Feng et al., 2009), and H2S levels in vessels, AT and circulation are altered in the presence of obesity or increased weight, suggesting that obesity‐related changes in AT's secretory profile may affect the production and levels of H2S (Candela et al., 2016). Indeed, studies have further shown a disparity in H2S production by PVAT in acute versus chronic obesity (Beltowski, 2013). Thus, while systemic changes in H2S may affect the vasculature, PVAT‐derived H2S may have particular importance in obesity‐related vascular disease, especially as PVAT‐derived H2S has direct paracrine, vasodilatory effects on the vascular wall (Fang et al., 2009). The mechanisms behind these paracrine, vascular effects of H2S may include changes in NO production from NOSs (Polhemus and Lefer, 2014) or direct S‐sulfhydration or persulfidation of key cysteine residues on membrane ion channels (Paul and Snyder, 2012), but further human studies are needed.

As local H2S originating from AT depots such as PVAT could be responsible for paracrine effects on the vasculature, H2S may be an interesting therapeutic target for vascular disease. Modulating local levels of H2S via donors may be one approach, but these donors have limitations: the half‐life of free H2S is only minutes and thus will need to be replenished to maintain bioavailability, especially as H2S can be oxidized in biological systems (Wallace and Wang, 2015). Targeting the biosynthetic enzymes of H2S, CSE and CBS, may also pose challenges as these enzymes belong to an evolutionarily conserved pathway, the reverse trans‐sulfuration pathway (Wallace and Wang, 2015), thus influencing these enzyme activities in humans, even with selective inhibitors, may have unintended side‐effects, such as affecting substrate homocysteine levels which has been associated with cardiovascular disease risk (Paul and Snyder, 2012).

Nonetheless, it is already known that some current drugs (e.g. non‐steroid anti‐inflammatory drugs (NSAIDs), sulfhydrated ACE inhibitors (ACEi) and PDE5) may mediate part of their effects through H2S and, furthermore, some drugs like atorvastatin specifically increase PVAT‐derived H2S (Beltowski, 2015), corroborating H2S's therapeutic potential. On the other hand, the sulfide prodrug resveratrol has only displayed limited cardiovascular benefit in clinical studies (Gliemann et al., 2016), implying that its effects may depend upon the underlying disease state or pharmacokinetic limitations. As such, further research into modulating AT‐derived H2S provides an exciting avenue to explore novel pharmacological targets against vascular disease pathogenesis (Figure 1).

Insulin resistance, Glucagon‐like peptide 1 (GLP‐1) and dipeptidyl peptidase (DPP) 4

There is a close relationship between insulin resistance and AT biology such that identifying ways to target peripheral insulin resistance in the vascular wall and AT may convey additional benefits beyond modulating systemic insulin resistance status. In particular, regulation of PVAT biology may ameliorate microvascular dysfunction and improve overall insulin sensitivity (Karaca et al., 2014) as drugs that are currently used as insulin sensitizers, such as metformin, have been shown to influence the biology of PVAT, as illustrated in Figure 1. Indeed, treatment of fructose‐fed rats with metformin restored the dysregulated adipocytokine expression profile of PVAT and attenuated the loss of endothelium‐dependent, acetylcholine‐mediated vasorelaxation ex vivo (Sun et al., 2014). On the other hand, PPARγ agonists, having been previously described as important regulators of AT function in terms of lipid storage, adipocytokine secretion, differentiation and inflammation, exert their biological effects, in part, by improving insulin sensitivity of AT (Wahli and Michalik, 2012). These findings suggest that PVAT function may be influenced by local insulin resistance, detrimentally affecting vascular biology. Thus, efficient targeting of insulin signalling in PVAT may be beneficial over holistic targeting of systemic insulin resistance (Figure 1).

GLP‐1 has recently emerged as an exciting multi‐layered signalling molecule with a variety of potential target tissues and a wide range of receptor‐mediated as well as non‐receptor‐mediated cellular effects (Cantini et al., 2016). GLP‐1 as well as a variety of GLP‐1 receptor ligands are believed to have anti‐inflammatory and antioxidant effects in the vasculature, inhibiting NADPH‐oxidase activity and stimulating AMPK and eNOS activation (Cantini et al., 2016). Recent findings of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial have confirmed the beneficial role of GLP‐1 signalling by demonstrating favourable cardiovascular outcomes in diabetic patients who were treated with the GLP‐1 receptor agonist liraglutide (Marso et al., 2016). In terms of the potential role(s) of GLP‐1 in AT biology, it is unclear whether AT is able to secrete GLP‐1, or if it expresses GLP‐1 receptors. However, GLP‐1 and its agonist analogues apparently have a variety of direct effects on AT biology, ranging from reduced lipid accumulation (Meier, 2012) to stimulation of adipogenesis (Challa et al., 2012). Additionally, GLP‐1 receptor agonists up‐regulate adiponectin expression (Kim Chung le et al., 2009) and promote M2 macrophage polarization (Shiraishi et al., 2012). The specific effects of these agents on PVAT and whether they can be involved in paracrine crosstalk loops between PVAT and the vascular wall have still to be established.

The enzyme responsible for cleavage of circulating GLP‐1, the peptidase DPP4, has been targeted with inhibitors to promote anti‐hyperglycaemic actions (Pratley and Salsali, 2007), and it is reasonable to assume, consequently, that the effects of DPP4 inhibitors on AT and cardiovascular disease will derive from the concomitant potentiation of GLP‐1 actions. While this may be true, recent evidence suggests that DPP4 inhibitors may also have a variety of direct effects on AT and the vasculature, independent of GLP‐1 signalling. Indeed, DPP4 has recently been revealed as a novel adipocytokine, the expression of which is elevated in visceral fat of obese patients, and is positively correlated with subcutaneous and visceral adipocyte size (Lamers et al., 2011), thus providing a novel link between AT biology and the metabolic syndrome. As DPP4 inhibitors have displayed a range of beneficial antioxidant and anti‐inflammatory effects on the vasculature as well (Fadini and Avogaro, 2011), targeting of DPP4 may be a crucial regulator of the crosstalk between PVAT and the vascular wall (Figure 1).

Pro‐inflammatory cytokines

Pro‐inflammatory cytokines are a key feature of vascular disease pathogenesis. Such cytokines are abundantly produced in inflamed PVAT, potentially facilitating the establishment of local inflammation and disease progression (Rajsheker et al., 2010). Consequently, efficient targeting of PVAT‐derived pro‐inflammatory adipocytokines may have a significant vasoprotective potential.

Currently, there is no established effective way to directly target local inflammation within PVAT, as existing anti‐inflammatory strategies (such as the anti‐TNF monoclonal antibodies Infliximab and Etanercept) exert mainly systemic vascular effects (Booth et al., 2004), partly via elevation of circulating adiponectin levels (Nishida et al., 2008). Nanotechnology has now emerged as a novel scientific field utilizing a variety of nanoparticles to offer targeted drug delivery options (Psarros et al., 2012), and as such it could allow for direct targeting of PVAT. Indeed, peptide‐conjugated nanoparticles have recently been revealed as a successful means of specifically targeting AT (Xue et al., 2016). Although it is unclear whether similar methods could be applied specifically to PVAT, they certainly appear as promising potential tools for efficient and specific therapeutic interventions.

Some drugs that are already frequently used in the treatment of cardiovascular disease exert pleiotropic, anti‐inflammatory effects and may target AT in exerting their effects. Apart from their roles in H2S signalling as described above, statins also decrease AT inflammation (Tousoulis et al., 2014), potentially by inhibiting activation of macrophages via toll‐like receptor 4 (TLR4) downstream events (Abe et al., 2008) (Figure 1). While the direct effects of statins on the inflammatory PVAT secretome are unknown, these findings suggest further exploration of such accepted drugs to establish potential, new ways to target local inflammation within PVAT (Antonopoulos et al., 2012).

Effects of common cardiovascular drugs on PVAT

Several drugs routinely prescribed for the management of cardiovascular disease are able to influence AT biology. Indeed, AT is an important activator of the renin‐angiotensin‐aldosterone system (RAAS) via secretion of angiotensinogen, thus increasing the production of angiotensin II (AngII) (Sowers, 2013). Obesity has also been associated with increased plasma levels of aldosterone (Whaley‐Connell and Sowers, 2011), and both AngII and aldosterone may inhibit physiological insulin signalling and promote local inflammation via activation of T cells and macrophages (Wei et al., 2009; Ohshima et al., 2012). Consequently, targeting of AT and the consequent blockade of the RAAS system may be significant components of the beneficial metabolic and cardiovascular effects of RAAS inhibitors such as ACEi, angiotensin receptor blockers (ARBs) and aldosterone inhibitors such as spironolactone (Sowers, 2013). Some ARBs are also able to act as partial PPARγ agonists, up‐regulating adiponectin expression (Watanabe et al., 2006). The effects of ACEi, ARB and aldosterone inhibitors are summarized in Figure 1.

Recent evidence suggests that aldosterone and mineralocorticoid receptor (MR) antagonists such as epleronone may have beneficial effects on vascular function, which could be mediated by their direct effects on AT biology. MR antagonists exert beneficial effects in terms of vascular redox state, systemic insulin sensitivity, vascular remodelling, endothelial function and AT inflammation (Guo et al., 2008; Nguyen Dinh Cat et al., 2011; Briones et al., 2012; Silva et al., 2015). Interestingly, adipocytes have been revealed to express both aldosterone and MR, which would in the case of PVAT allow for both autocrine and paracrine (towards the neighbouring blood vessels) aldosterone signalling to occur (Briones et al., 2012). On the other hand, aldosterone has detrimental direct effects on the vasculature (Briet and Schiffrin, 2013). Therefore, the beneficial effects of MR antagonists observed in the previous experimental settings could, in theory, originate from the blockade of aldosterone signalling either in the vasculature or in AT (or both). Recent work has addressed this issue by utilizing an AT‐specific MR‐overexpressing mouse model; the direct action of aldosterone on AT was associated with metabolic syndrome, insulin resistance, a pro‐inflammatory phenotype of the AT and paracrine effects of PVAT on the vasculature (Nguyen Dinh Cat et al., 2016). These findings identify aldosterone as a link between AT and vascular biology. On the other hand, not all studies have demonstrated beneficial effects for MR antagonist treatment on cardiovascular disease prognosis (Parviz et al., 2015), warranting further investigation.

In contrast to aldosterone antagonists, thiazide diuretics have reportedly detrimental effects on glucose and lipid metabolism, worsening insulin sensitivity, a process that may be at least partially dependent upon activation of the RAAS system (Raheja et al., 2012). Therefore, a combination of thiazide diuretics with inhibitors of the RAAS system such as ARBs may be beneficial in the management of cardiovascular disease in diabetic patients, in order to preserve insulin sensitivity (Sowers et al., 2010). However, the extent to which thiazide diuretics directly affect AT depots and their secretome is not adequately explored. It has been suggested that chlorothiazide down‐regulates expression of adiponectin in 3T3‐L1 adipocytes (Brody et al., 2009), an effect with potentially detrimental cardiovascular effects (Figure 1). Further knowledge of the direct effects of thiazide diuretics on AT, as well as the systemic consequences of these effects is needed to optimize the administration of these agents.

β‐blockers are another class of drugs that, although used extensively in a variety of cardiovascular diseases, have been associated with a variety of metabolic side effects such as obesity and insulin resistance (Pischon and Sharma, 2001). Non‐selective blockade of α‐adrenoceptors which results in inhibition of lipase activity, has been implicated in such effects (Cruickshank, 2000). On the other hand, β‐blockers also have the ability to suppress excessive sympathetic activity and stimulation of the RAAS system, an effect that would be beneficial in terms of inflammation and insulin resistance (Sowers, 2013). It seems that the overall metabolic effects of β‐blockers depend on the specific characteristics of individual members of this heterogeneous drug class, with third generation β‐blockers being associated with antioxidant properties and fewer non‐selective side effects (Ozyildiz et al., 2016). Although there is evidence that β‐blockers exert direct metabolic effects on AT, ranging from the stimulation of mitochondrial biogenesis to induction of adipogenesis (Wong et al., 2012; Huang et al., 2013), the extent to which these drugs are able to modulate the secretome of distinct AT depots in vivo is unknown.

Conclusion

Recent progress in our understanding of AT biology in health and disease has revealed that AT is, in fact, an active endocrine organ subject to complex regulatory mechanisms and able to affect vascular biology in many direct and indirect ways. PVAT in particular, due to its anatomical proximity to the wall of most arteries, is now believed to be of unique functional significance for vascular physiology and pathophysiology, with its paracrine roles being crucial. Many reports have identified the ability of PVAT to regulate vascular tone as well as other aspects of vascular function via its secretome. These abilities are altered in states of obesity and vascular disease, where the quantity and functional phenotype of PVAT differ, potentially resulting in a net pre‐atherogenic secretome inducing inflammation, vasoconstriction, endothelial dysfunction and proliferation and migration of VSMCs, thus propagating vascular disease. Importantly, PVAT may also act as a recipient of a variety of signals such as oxidation products from the vascular wall, allowing it to dynamically ‘sense’ alterations of vascular biology and modify its secretome appropriately. Such paracrine feedback loops that provide intrinsic rescue mechanisms may be dysregulated in vascular disease, and may thus comprise potentially novel and attractive therapeutic targets for pharmacological intervention. However, at present, increased understanding of the underlying mechanisms is needed to allow the development of new therapeutic strategies for the prevention and treatment of cardiovascular disease, by targeting PVAT.

Conflict of interest

C.A. and I.A. are recipients of an unrestricted grant by Sanofi.

Acknowledgements

Prof Antoniades is funded by the British Heart Foundation (FS/16/15/32047), the National Institute for Health Research Oxford Biomedical Research Centre and the European commission (ITN network RADOX‐GA‐316738).

Akoumianakis, I. , Tarun, A. , and Antoniades, C. (2017) Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets. British Journal of Pharmacology, 174: 3411–3424. doi: 10.1111/bph.13666.

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