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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2016 Nov 18;174(20):3388–3397. doi: 10.1111/bph.13648

Comparisons between perivascular adipose tissue and the endothelium in their modulation of vascular tone

K E Zaborska 1, M Wareing 2, C Austin 3,✉
PMCID: PMC5610163  PMID: 27747871

Abstract

The endothelium is an established modulator of vascular tone; however, the recent discovery of the anti‐contractile nature of perivascular adipose tissue (PVAT) suggests that the fat, which surrounds many blood vessels, can also modulate vascular tone. Both the endothelium and PVAT secrete vasoactive substances, which regulate vascular function. Many of these factors are common to both the endothelium and PVAT; therefore, this review will highlight the potential shared mechanisms in the modulation of vascular tone. Endothelial dysfunction is a hallmark of many vascular diseases, including hypertension and obesity. Moreover, PVAT dysfunction is now being reported in several cardio‐metabolic disorders. Thus, this review will also discuss the mechanistic insights into endothelial and PVAT dysfunction in order to evaluate whether PVAT modulation of vascular contractility is similar to that of the endothelium in health and disease.

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

BAT

brown adipose tissue

CSE

cystathionine γ‐lyase

CVD

cardiovascular disease

H2O2

Hydrogen peroxide

H2S

hydrogen sulphide

MLC

myosin light chain

O2−

superoxide

PVAT

perivascular adipose tissue

PVRFs

PVAT‐derived relaxant factors

VSM

vascular smooth muscle

WAT

white adipose tissue

Tables of Links

TARGETS
Other protein targets a Enzymes e
TNF‐α Adenylate cyclase
GPCRs b AMPK
IP receptor COX‐1
Voltage‐gated ion channels c COX‐2
KV channels CSE
Ligand‐gated ion channels d eNOS
BKCa channel Guanylyl cyclase
IKCa channel NOS
KCa channel PKA
KATP (Kir6.1) channel PKG
SKCa channel
LIGANDS
5‐HT L‐arginine
Adiponectin MCP‐1 (CCL2)
ATP NO
cAMP Noradrenaline
cGMP PGD2
GTP PGE2
H2O2 PGF2α
IL‐6 PGI2
Indomethacin TXA2
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These Tables list key protein targets and ligands in this article that 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,d,eAlexander et al., 2015a,b,c,d,e).

Introduction

Blood vessels are composed of three layers: tunica adventitia, tunica media and tunica intima, and many blood vessels are surrounded by perivascular adipose tissue (PVAT). The adventitia mainly contains connective tissue, while the tunica media (especially in arteries) consists mainly of vascular smooth muscle (VSM). The endothelium, the inner layer of all blood vessels, consists of a thin layer of squamous endothelial cells. Vascular contractility is primarily regulated by the level of contraction of the VSM that can be influenced by the endothelium. The recent discovery of the anti‐contractile nature of PVAT suggests that the fat around blood vessels can also modulate vascular contractility rather than merely providing a structural support. The principal role of VSM is regulation of blood vessel tone/diameter and blood pressure (Owens et al., 2004). VSM contraction may be modulated by vasoconstrictive hormones, vasodilating agents as well as electrical and mechanical stimuli. Some vasoconstricting agonists can activate the RhoA/Rho‐kinase pathway, which sensitizes the VSM contractile machinery to Ca2 + inducing greater contraction at lower intracellular Ca2 + levels; mechanistically this is achieved via inhibition of dephosphorylation of the MLC by myosin light chain phosphatase (Fukata et al., 2001). Increasing [Ca2 +]i also activates potassium (K+) channels, which results in VSM hyperpolarisation and subsequent vasodilatation (Eichhorn and Dobrev, 2007).

The endothelium functions as a semi‐selective barrier between the circulating blood in the lumen and the tissues of the vessel wall and extracellular compartment. Fluid and solutes easily pass across the endothelial layer, and white blood cells may also pass into and out of the blood stream. The endothelium is an important endocrine and paracrine organ that plays a key role in the regulation of vascular tone by releasing factors that modulate VSM contractility (Edwards et al., 2010). Furchgott and Zawadzki (1980) were the first to observe a role for the endothelium in the control of vascular contractility when they demonstrated the release of a diffusible factor, an endothelium‐derived relaxing factor, which promoted vasorelaxation (Furchgott and Zawadzki, 1980). Numerous research studies have shown that the endothelium releases both vasodilating (such as endothelium‐derived hyperpolarising factors, the prostaglandin PGI2 and NO) and vasoconstricting agents (such as endothelin‐1, TXA2 and angiotensin II) and, in the healthy individual, controls vascular tone by balancing their release (see Feletou and Vanhoutte, 2006). The endothelium can modulate VSM contraction via myo‐endothelial gap junctions, which permit ions and polar molecules to pass from cell to cell via an aqueous central pore (Fleming, 2000). It is well known that the endothelium plays a key role in the control of vascular function as its dysfunction is a major factor in the pathogenesis of many cardiovascular diseases (CVD) including hypertension and atherosclerosis (Shaul, 2002; Gollasch and Dubrovska, 2004; Nagata et al., 2004; Boily et al., 2008; Horman et al., 2008; Malinowski et al., 2008; Maenhaut and Van de Voorde, 2011). Endothelial cell dysfunction is also associated with diabetes and metabolic syndrome (Kim et al., 2006; Avogaro et al., 2011).

Although the importance of the endothelium in the regulation of vascular tone is undisputed, it is now clear that it is not the only significant regulator of arterial tone. PVAT surrounds many blood vessels in the body; it is very abundant around the aorta and mesenteric arteries, but it is absent in the cerebral vasculature and microvasculature (Horman et al., 2008; Miao and Li, 2012). At first it was thought to provide mechanical support. However, since the original publication by Soltis and Cassis in 1991 (Soltis and Cassis, 1991), a number of groups have demonstrated that PVAT can significantly influence vascular contractility; these include Lohn's observations on the existence of a adipocyte derived relaxing factor (ADRF) in 2002 (Lohn et al., 2002). PVAT is composed of both white (WAT) and brown adipose tissue (BAT). WAT serves mainly as an energy store (Miao and Li, 2012), whereas BAT is mainly associated with thermogenesis, is more vascularized and is highly active metabolically (Smith and Roberts, 1964). The ratio of WAT/BAT is not constant across vascular beds; for example, PVAT in rats and mice surrounding the abdominal aorta and mesenteric vessels is mainly composed of WAT, while PVAT associated with the thoracic aorta is predominantly BAT (Frontini and Cinti, 2010; Cinti, 2011; Miao and Li, 2012). Interestingly, recently it has been proposed that adipocytes can undergo ‘browning’ (Young et al., 1984), a process whereby WAT transforms into BAT via activation of the PI3K/Akt and AMPK signalling pathways (Than et al., 2015).

PVAT consists of a variety of cells, including adipocytes, macrophages, lymphocytes, endothelial cells, fibroblasts and adipocyte stem/progenitor cells. PVAT is an endocrine organ that releases free fatty acids/non‐esterified fatty acids by lipolysis and also secretes a number of bioactive proteins, called adipokines. These adipokines have autocrine, paracrine and endocrine functions, and they can modulate vascular function under normal physiological conditions. Some adipokines including adiponectin, nesfatin, vaspin, chemerin and omentin may be involved in the regulation of cardiovascular function; however, the mechanisms are still unclear and, for some, their expression in PVAT has not been conclusively demonstrated (Yamawaki, 2011).

PVAT has also been shown to modulate vascular contractility through the release of PVAT‐derived relaxant factors (PVRFs) (Chang et al., 2013). Although it is still unclear how PVRFs exert their anti‐contractile effects, a number of potential PVRFs have been suggested including hydrogen sulphide H2S (Wojcicka et al., 2011), NO (Gao et al., 2007) and angiotensin 1–7 (Lee et al., 2009). Data from a number of groups suggest that this PVAT‐induced vasodilatation is not species or vessel subtype specific (Soltis and Cassis, 1991; Dubrovska et al., 2004; Gollasch and Dubrovska, 2004; Guzik et al., 2007; Greenstein et al., 2009). In addition to endothelial dysfunction, it has also been demonstrated that PVAT dysfunction is evident in many cardio‐metabolic diseases, including hypertension and obesity (Greenstein et al., 2009; Zou et al., 2016).

The endothelium is a well‐established modulator of vascular tone; however, more recently, PVAT has also been shown to control arterial contractility. Both the endothelium and PVAT play a part in the pathogenesis of many vascular diseases. Therefore, this review will focus on the control of vascular tone by PVAT and its similarities in the control of contractility by the endothelium.

Anti‐contractile effects

Both the endothelium and PVAT release vasodilators and vasoconstrictors with the net effect in a healthy individual tending towards vasodilatation. The landmark discovery of NO (Palmer et al., 1987), which has subsequently been demonstrated to be the main vasodilator released by the endothelium, established its key role in the endothelium‐dependent modulation of vascular contractility. More recently, PVAT has been similarly shown to have the ability to reduce vascular contractility through the release of PVRFs (Lohn et al., 2002). The mechanisms by which PVAT exerts this anti‐contractile effect are not as well established as the control of vascular contractility by the endothelium; however, a number of studies have noted that the endothelium and PVAT release many common vasoactive factors that modulate vascular tone, and these are discussed below.

Nitric oxide

NO is a free‐radical, endogenous gas that is involved in many physiological and pathophysiological processes of the cardiovascular system. In the endothelium, NO is synthesized from endothelial NOS (eNOS), which is sensitive to changes in [Ca2 + i] concentration. eNOS catalyses the oxidation of L‐arginine into NO and L‐citrulline, a reaction requiring the presence of cofactors such as calmodulin, flavin mononucleotide, flavin adenine dinucleotide and nicotinamide adenine dinucleotide phosphate. eNOS is regulated by phosphorylation at two major sites with opposing effects; Ser1177 phosphorylation leads to its activation while Thr495 phosphorylation decreases its activity (Dudzinski and Michel, 2007).

Palmer et al. showed that endothelial cells are able to generate NO that is responsible for the vasodilating properties of the endothelium‐derived relaxing factor (Palmer et al., 1987) described 7 years earlier (Furchgott and Zawadzki, 1980). NO regulates basal vascular tone and causes relaxation of VSM by stimulation of soluble GC to produce cGMP (Murad, 1986). Increased cGMP levels activate calcium sensitive potassium channels (KCa channels) and KATP channels leading to a decreased [Ca2 +]i concentration and subsequent relaxation of VSM (Warner et al., 1994). NO can also directly activate KCa channels (Bolotina et al., 1994).

eNOS is expressed in adipocytes (Ribiere et al., 1996) and has now also been demonstrated in PVAT (Gao et al., 2007). The anti‐contractile effect of PVAT in various vascular beds – including rat aorta (Gao et al., 2007), mouse mesenteric arteries (Lynch et al., 2013), rat mesenteric artery (Bussey et al., 2016; Zaborska et al., 2016) and human subcutaneous arteries – has been shown to be abolished by NOS inhibition (Greenstein et al., 2009; Aghamohammadzadeh et al., 2015). NO leads to increased cGMP levels and subsequent protein kinase G activation (Rapoport and Murad, 1983). The anti‐contractile effect of PVAT is also lost in mesenteric arteries from protein kinase G knockout mice (Withers et al., 2014).

To summarize, inhibition of NOS has been shown to modulate the effects of both the endothelium and PVAT on vascular tone suggesting that NO is an important vasodilator, which is synthesized and released from both the endothelium and PVAT.

Prostacyclin

Prostaglandins were one of the first vasoactive substances produced by the vasculature to be identified (Moncada et al., 1977). They are synthesized from arachidonic acid by two COX enzymes (COX1 and COX2). The five primary prostaglandins include PGE2, prostacyclin (PGI2), PGD2, PGF2α and TXA2. These species modulate vascular contractility by activation of specific PG receptors either inducing vasoconstriction (PGF2α; TXA2) or vasodilatation (PGD2; PGI2) or both (PGE2). PGI2 is the most abundant prostaglandin produced by the endothelium (Moncada et al., 1977) and is an important endogenous vasodilator that binds to IP receptors on the VSM. Via stimulation of the GS subunit, activation of adenylate cyclase promotes cAMP production and subsequent VSMC relaxation (Alfranca et al., 2006). This prostacyclin‐mediated vasorelaxation is associated with the opening/activation of potassium channels in the VSM cells, including ATP‐sensitive potassium channels (KATP) and delayed‐rectifier potassium channels (Kdr); both subtypes are sensitive to the increasing intracellular cAMP levels (Li et al., 1997).

Both COX1 and COX2 are also expressed in adipocytes (Bolduc et al., 2004), endothelial cells (Hla and Neilson, 1992) and macrophages (Fels et al., 1986); all of which are present in PVAT. Adipocytes also serve as a major source of PGs induced by catecholamine stimulation (Shaw and Ramwell, 1968) suggesting PVAT has the ability to produce and release prostaglandins and that these PGs may be involved in the mediation of the anti‐contractile effect of PVAT on the vascular tone. Experimentally, the data are inconsistent; the early work by Lohn et al. (2002) suggested that COX is not an ADRF, as PVAT still exerted an anti‐contractile effect in response to 5‐HT stimulation, in the presence of a non‐specific COX inhibitor, indomethacin, in the rat aorta (Lohn et al., 2002), while others have determined that COX does contribute to the noradrenaline‐induced anti‐contractile effect of PVAT in mouse mesenteric artery (Lynch et al., 2013) and human saphenous vein (Ozen et al., 2013). The latter data suggests that prostaglandins (specifically PGE2 and PGI2) only mediate noradrenaline‐induced vasodilatation by PVAT (Ozen et al., 2013) (i.e. the involvement of products of COX enzymic activity is agonist‐dependent). PGI2 has also been shown to be responsible for the PVAT‐mediated endothelium‐dependent vasodilatation in mouse carotid artery (Chang et al., 2012). TXA2 release from mouse aortic PVAT is increased in obesity in response to 5‐HT stimulation (Meyer et al., 2013).

To summarize, both the endothelium and PVAT modulate vascular contractility by releasing a variety of prostaglandins.

Hydrogen peroxide

Hydrogen peroxide (H2O2) is a ROS produced in the endothelium (Breton‐Romero and Lamas, 2014) either by spontaneous dismutation of superoxide (O2 −) or dismutation of O2 − by superoxide dismutases. It is clear from the literature that H2O2 significantly alters vascular tone; however, the data are inconsistent as some studies report vasodilatation (Matoba et al., 2000; Matoba et al., 2002; Shimokawa and Matoba, 2004; Liu et al., 2011) while others vasoconstriction (Gao and Lee, 2005; Mills et al., 2009; Suvorava and Kojda, 2009). H2O2 has been shown to vasodilate mouse and human mesenteric arteries (Matoba et al., 2000; Matoba et al., 2002); these vasodilator effects of H2O2 may be mediated by activation of large conductance calcium‐activated potassium channels (BKCa) on the VSM cells (Liu et al., 2011) and activation of endothelial NO production (Drummond et al., 2000).

H2O2 has also been shown to be produced in adipocytes (Luoma et al., 1998) and has been proposed as a PVRF. PVAT‐intact rat aortae incubated with catalase (a H2O2 scavenger) show enhanced vessel contraction (Gao et al., 2007) suggesting that H2O2 may play a role in the anti‐contractile effect of PVAT. This PVAT‐derived H2O2 exerts vasodilatation through activation of soluble guanylyl cyclase within VSMC (Gao et al., 2007).

To summarize, H2O2 modulates vascular contractility. Endothelium‐derived H2O2 can induce either vasoconstriction or vasodilatation depending on the concentration, species and vessel type. However, PVAT‐derived H2O2 has only been shown to contribute to the anti‐contractile effect through activation of soluble GC in VSM.

Hydrogen sulphide

H2S is a gaseous transmitter synthesized from L‐cysteine by the enzyme cystathionine γ‐lyase (CSE) (Kimura, 2011). Endothelium‐dependent relaxation has been shown to be impaired in CSE−/− knockout mice (Mustafa et al., 2011), suggesting that H2S is a vasorelaxant produced/released by the endothelium. Additionally, CSE expression has been demonstrated in mouse endothelial cells, where it is activated by Ca2 +/calmodulin (Yang et al., 2008). H2S induces relaxation by activating endothelial SKCa and IKCa channels; it has also been shown to activate KATP channels in VSM cells (Zhao et al., 2001; Mustafa et al., 2011). CSE expression has also been demonstrated in rat aortic PVAT where it has been proposed to be responsible for the anti‐contractile effects of PVAT (Kohn et al., 2012). It has also been suggested that H2S mediates the anti‐contractile effect of PVAT via opening of KV channels (Schleifenbaum et al., 2010). However, the minutiae of how this gas acts within the cell to promote vasodilatation are yet to be fully elucidated.

To summarize, H2S is a gaseous relaxant that activates K+ channels when released from the endothelium. It may contribute to the anti‐contractile effect of PVAT, although the mechanism is currently unknown.

Potassium channels

VSM membrane potential is the major determinant of vascular tone due to its influence on voltage‐gated Ca2 + channels, which permit Ca2 + entry into the cell and subsequent constriction. K+ channels are key regulators of the membrane potential, their activation leads to K+ efflux and closure of voltage‐dependent Ca2 + channels, which results in vasodilatation. However, K+ channel inhibition results in depolarisation and subsequently contraction. SKCa and IKCa channels are expressed in endothelial cells (Marchenko and Sage, 1996; Burnham et al., 2002) and were proposed to modulate VSM contraction via endothelial hyperpolarization that can be transmitted to VSM through myo‐endothelial gap junctions (Marrelli et al., 2003; Gluais et al., 2005). Activation of these channels also results in an increase in extracellular K+, which promotes hyperpolarization of VSM through activation of Na+/K+‐ATPase or inwardly rectifying K+ channels (Kir) (Weston et al., 2002).

Experimentally, an increase in extracellular K+ concentration (60 mM KCl) abolishes the anti‐contractile effect of PVAT, suggesting that K+ channels are involved in the modulation of vascular tone by PVAT [since a high extracellular K+ concentration attenuates the effects of K+ channels by reducing the K+ gradient across the cell membrane (Lohn et al., 2002)]. In addition to this, PVAT also hyperpolarises the membrane potential in rat mesenteric (Verlohren et al., 2004; Weston et al., 2013) and gracillis muscle arteries (Zavaritskaya et al., 2013) further supporting the role of K+ in the anti‐contractile capacity of PVAT. Moreover, BKCa and KV channels have also been proposed to modulate the effect of PVAT on vascular contractility (Verlohren et al., 2004; Galvez et al., 2006; Schleifenbaum et al., 2010; Lynch et al., 2013) in numerous vascular beds.

To summarize, activation of K+ channels may be involved in the anti‐contractile effects of both PVAT and the endothelium on vascular contractility.

Endothelial/PVAT dysfunction

Resistance artery dysfunction observed in obesity can arise from, and contribute to, hypertension (de Jongh et al., 2004; Frisbee, 2005) leading to a ‘vicious cycle’ in which the resistance vasculature maintains or even augments the initial rise in blood pressure (Levy et al., 2001). Obesity has detrimental effects on health; it can lead to insulin resistance, the metabolic syndrome, Type 2 diabetes mellitus and increased blood pressure, all being major risk factors for CVD.

Endothelial dysfunction refers to the inability of the endothelium to maintain vascular homeostasis resulting from an imbalance in the production of vasodilating and vasoconstricting factors from the endothelium. This dysfunction results in a shift towards the production of vasoconstricting factors, thus increasing peripheral resistance and consequently blood pressure (Drexler, 1998). This impairment in endothelial function is observed early in the progression of CVD; hence, endothelial dysfunction is an early predictor of future CVD, hypertension and atherosclerosis (Schachinger et al., 2000). A blunted endothelium‐dependent response to vasodilating agents (such as acetylcholine) has been reported in studies on hypertension and obesity (Aalkjaer et al., 1987; Izzard et al., 1996; Jonk et al., 2007).

PVAT dysfunction is also now becoming evident in disease states. Age, environmental conditions and nutritional status also change the percentage of the cellular subtypes within PVAT. Normal adipose tissue tends to be in a non‐inflammatory state, while obesity results in abnormal adipokine production, oxidative stress, hypoxia and inflammation of the adipose tissue (Achike et al., 2011). PVAT dysfunction is also associated with an up‐regulation of vasoconstricting factors (Almabrouk et al., 2014) and has been implicated in obesity (Greenstein et al., 2009; Meijer et al., 2015) and hypertension (Aghamohammadzadeh et al., 2015). PVAT dysfunction has been shown to contribute to the obesity‐related endothelial dysfunction (Ketonen et al., 2010) and smooth muscle cell dysfunction (Greenstein et al., 2009).

Obesity‐related hypertension is associated with endothelial (de Jongh et al., 2004) and PVAT dysfunction (Aghamohammadzadeh et al., 2015), and several factors have been proposed to play a role and are discussed in more detail below.

Endothelial/PVAT dysfunction – nitric oxide

The endothelial dysfunction observed in obesity is associated with reduced NO bioavailability due to increased production of ROS (Bakker et al., 2000). eNOS uncoupling leads to the production of O2 − (Kalinowski and Malinski, 2004) instead of NO. O2 − can cause vasoconstriction directly due to the production of peryoxynitrate (from O2 − + NO), which in turn increases the production of vasoconstricting prostaglandins by interacting with prostaglandin endoperoxide synthase (Goodwin et al., 1999); O2 − can also cause vasoconstriction indirectly by reducing NO bioavailability. In obesity, endothelial dysfunction is associated with the decreased NO bioavailability due to eNOS uncoupling (Lobato et al., 2011).

Similarly, obesity‐linked PVAT dysfunction is also associated with reduced NO bioavailability from PVAT (Bussey et al., 2016), which is responsible for the reduced anti‐contractile effect observed in obesity. Uncoupling of eNOS and increased O2 − production were also proposed to contribute to the PVAT‐induced endothelial dysfunction in obese mice (Xia et al., 2016).

Endothelial/PVAT dysfunction – prostanoids

Another mechanism involved in endothelial and PVAT dysfunction in obesity is the impairment of prostaglandin release. Both COX1 and COX2 activities are increased in the endothelium from obese rats; however, in lean rats, COX2 does not influence the endothelial function, suggesting that the shift in COX2 activity observed in obesity contributes to the endothelial dysfunction (Sanchez et al., 2010). Indeed the increased production of the TXA2 and reduced PGI2 release observed in obesity were attributed to the increased prostaglandin production from arachidonic acid by COX2, induced by inflammation (Lobato et al., 2011).

Obesity is also associated with increased activity of both COX1 and COX2 in adipose tissue (Hsieh et al., 2010; Farb et al., 2014). Recently, Meyer et al. (2013) reported that obesity is associated with increased COX activity that leads to the release of a pro‐contractile factor (TXA2) from PVAT, suggesting that COX activity may play a part in obesity‐induced PVAT dysfunction (Meyer et al., 2013).

Endothelial/PVAT dysfunction – K+ channels

Various potassium channels (such as KCa, Kir and KV) have been implicated in the endothelial dysfunction observed in obesity and hypertension (reviewed by (Climent et al., 2014). The diminished anti‐contractile effect of PVAT observed in hypertension can be restored using KCNQ channel openers in rat Gracilis muscle arteries from spontaneously hypertensive rats, suggesting that a dysfunction in K+ channels activation mediates the altered PVAT regulation of vascular tone (Zavaritskaya et al., 2013).

Endothelial/PVAT dysfunction – inflammation

Obesity also leads to an increased production of the pro‐inflammatory cytokines, such as monocyte chemoattractant protein‐1 (also known as CCL2), TNF‐α and IL‐6 by endothelial cells and pre‐adipocytes (Wellen and Hotamisligil, 2003). Obesity‐linked inflammation contributes to endothelial dysfunction (Ziccardi et al., 2002) by stimulating ROS generation and reducing NO bioavailablity (Virdis et al., 2011). Local inflammation and hypoxia of PVAT observed in obesity were also proposed to attenuate its anti‐contractile properties (Greenstein et al., 2009).

In summary, endothelial dysfunction is well recognized as an important predictor of CVD, but more recently, PVAT has also been proposed to play a role. Obesity‐linked PVAT and endothelial dysfunction are associated with altered NO and prostaglandin production, as well as inflammation and impaired K+ channel activation.

Conclusions

The endothelium and PVAT produce both vasodilating and vasoconstricting factors that have been clearly demonstrated to modulate vascular contractility. There are many common pathways by which the endothelium and PVAT control vascular tone; these include NO, prostaglandins, K+ channels, H2O2 and H2S (Figure 1). An imbalance in the production of vasodilating and vasoconstricting factors that promotes an increased release of the latter leads to endothelial and PVAT dysfunction. These cellular dysfunctions are observed in both human obesity and animal models of disease, and the mechanisms involved are similar in both the endothelium and PVAT. The role of the endothelium in the control of vascular contractility is well established, more so than for PVAT; however, recent studies have shown that PVAT releases similar vasoactive substances to those released from the endothelium. The ability of PVAT to alter vascular reactivity by the production and release of vasoactive factors would ensure that the perfusion of local blood vessels could be attuned by PVAT to more accurately meet the needs of the tissues. However, more research is needed with regards to the modulation of vascular tone mediated by PVAT, as the mechanisms have yet to be fully elucidated.

Figure 1.

Figure 1

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The vasodilating factors released by the endothelium and PVAT. The conversion of L‐arginine into NO by endothelial (e) NOS in both the endothelium and PVAT stimulate soluble guanylyl cycles (sGC) in the VSM, which in turn converts GTP into cGMP. PKG activation leads to vasorelaxation. The enzymatic activity of COX leads to PGI2 production within the endothelium and PVAT. Endothelial PGI2 stimulates AC, which converts ATP into cAMP. PKA is then activated, which leads to relaxation of the VSM. Increasing levels of cAMP can also activate delayed rectifier potassium channels (Kdr) ATP‐sensitive potassium channels (KATP). PVAT‐derived PGI2 causes relaxation of VSM via an unknown mechanism; however, it is most likely to stimulate AC. H2O2 is released by both the endothelium and PVAT and exerts its anti‐contractile effects via sGC activation within the VSM. Endothelial H2O2 can also directly activate KCa on the VSM. H2S mediates the anti‐contractile effects of PVAT via voltage‐gated potassium channels (KV) on VSM. Within the endothelium, H2S activates small‐conductance (SKCa) and intermediate‐conductance (IKCa) calcium‐activated potassium as well as KATP channels on VSM. Activation of SKCa and IKCa on the endothelium leads to hyperpolarisation, which can spread to VSM via myo‐endothelial gap junctions. Large‐conductance calcium‐activated potassium channels (BKCa) are also thought to mediate the anti‐contractile effect of PVAT.

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgements

K.E.Z. is a PhD student supported by the British Heart Foundation (FS/12/68/30006) and The Maternal & Fetal Health Research Centre receives support from Tommy's; let's talk baby.

Zaborska, K. E. , Wareing, M. , and Austin, C. (2017) Comparisons between perivascular adipose tissue and the endothelium in their modulation of vascular tone. British Journal of Pharmacology, 174: 3388–3397. doi: 10.1111/bph.13648.

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