Perivascular adipose tissue (PVAT) in atherosclerosis: a double-edged sword

Atherosclerosis is an inflammatory disease of the arteries characterized by lipid accumulation within the artery walls. In humans, atherosclerotic plaques are usually found in the aorta, the coronary arteries and cerebral arteries, but also in peripheral arteries [1]. Advanced atherosclerotic plaques grow large to block blood flow resulting in various cardiovascular diseases (CVD) including coronary heart disease (CHD), angina, carotid artery disease, peripheral artery disease and chronic kidney disease. Even though epidemiological and experimental studies have strengthened the pathophysiological associations between obesity and atherosclerosis [2, 3], the underlying causes of atherosclerosis remain unclear. Growing evidence suggest that atherosclerotic plaque formation begins with endothelial damage caused by factors released from adipose tissues to the circulation, promoting adhesions of circulating immune cells that initiate the progression of atherosclerosis [4, 5].

Adipose tissue is distributed throughout the body. In general, there are two main types of adipose tissues: white adipose tissue (WAT) and brown adipose tissue (BAT) [6, 7]. Historically, adipose tissue was recognized as a protective pad for neighboring organs. In recent years however, adipose tissue has emerged as a major endocrine organ which produces large amount of adipokines such as leptin, resistin, adiponectin and inflammatory cytokines [8‐10]. Excess lipid accumulation in WAT causes adipocyte hypertrophy and dysfunction, resulting in enhanced secretion of deleterious adipokines and inflammatory cytokines into the circulation, that subsequently impair the function of the endothelium in blood vessels [11, 12]. Unlike WAT, BAT can take-up lipids to produce heat by uncoupling oxidation on mitochondrial electron transportation chain, which contributes to clearance of plasma lipids and prevents storage of lipids in WAT and other organs [13]. Dysfunctional WAT might be positively associated with atherosclerosis development, whereas activation of BAT may protect against atherosclerosis development. This hypothesis is strengthened by evidence of reduced hypercholesterolaemia and atherosclerosis development upon BAT activation with β3-adrenergic receptor stimulation in hyperlipidemic mice [14]. Key milestones in BAT research are the discovery of active BAT sites in adult humans and the “browning” ability of WAT by hormonal or cold temperature stimuli [15‐18]. Browning of WAT is now defined as the third type of adipose tissue—beige adipose tissue (BeAT), which is characterized by high expression of the brown adipocyte marker uncoupling protein-1 (UCP-1) [19].

In addition to the classification of adipose tissues by their coloration, adipose tissues can also be categorized according to their anatomic locations. Perivascular adipose tissue (PVAT) is a type of adipose tissue which surrounds the blood vessels. Recently, PVAT characteristics resemble both BAT and WAT, it has been considered as an active component of the blood vessel walls, and involved in vascular homeostasis [20]. There are intensive studies regarding the relationship between PVAT and atherosclerosis [21, 22]. In this review, we will focus on the roles of PVAT in the pathophysiological progress of atherosclerosis (both pro- and anti-atherogenic effect) and its potential as a target for therapeutic intervention (Fig. 1).

Although surrounding adipose tissue is abundant in vascular trees of animals and humans, it was ignored for a long time. As pointed recently by Caroline Pond: “human and comparative anatomists still regarded it as too inconsistent and inconsequential to be worthy of topographic, functional or evolutionary study. It was always dissected off vessels and lymph nodes in pickled prosections” [23]. In 1982, Hausman and Richardson first described the histochemical and ultrastructural criteria of preadipocytes in perivascular location [24]. In 1984, de Souza et al. [25] described that the vessel’s sheaths and lamellae are formed by networks of collagen and elastic fibers. The perivascular area is filled by connective tissue, delimiting lobules of adipose tissue. Since then, there had been little research on the function of perivascular connective tissue until 1991 when Soltis and Cassis defined PVAT and its influence on rat aortic smooth muscle responsiveness [26]. In 2001, Okamoto et al. [27] reported the invasion of leukocytes into the perivascular adipose layer in response to angioplasty injury of coronary arteries, suggesting that PVAT inflammation might be associated with CVD.

In humans, the severity in spontaneous atherosclerosis may vary not only in different arteries but also in different segments of the same blood vessel [28]. Previous research, mainly in rodents, indicates that the appearance of PVAT varies by anatomic and metabolic context [29]. Current reports indicate that PVAT in the thoracic aorta is more similar to BAT, while PVAT in the abdominal aorta resembles both WAT-like and BAT-like phenotypes, which is referred as BeAT. Other smaller arteries are surrounded by WAT-like PVAT [30]. In humans, the coronary arteries are the most atherosclerosis-prone arteries with abundant of PVAT surrounding. In mice however, there is no PVAT surrounding the coronary arteries [30]. Of interest, mouse coronary arteries are resistant to atherosclerosis development [31], suggesting that the existence of PVAT may be associated with atherosclerosis development. However, the occurrence and development of atherosclerosis is influenced by many factors that determine the vascular susceptibility for atherosclerotic risk factors. Indeed, different segments of the aorta are differentiated from the distinct origins. It is unclear whether the atherosclerosis susceptibility of artery is associated with its origins. Similarly, different types of adipose tissue located at different anatomical depots may have their unique precursors.

The adipocytes in classical WAT such as subcutaneous WAT may be differentiated from mesenchymal stem cells (MSCs) in perivascular regions [32, 33]. Tang et al. [34] found that the majority of postnatal white adipocytes derived from prenatally peroxisome proliferator-activated receptor-γ (PPAR-γ) expressing lineage cells that are located in the stromal vasculature fraction (SVF). Gene-expression profiles showed that these PPAR-γ expressing lineage cells have a unique molecular signature and are phenotypically distinct from adipocytes and other stromal vasculature cells. Specifically, the SVF of harboring PPAR-γ expressing cells resembles blood vessels with expressions of mural cell markers smooth muscle actin (SMA), platelet-derived growth factor receptor, β polypeptide (PDGFRβ), and neural/glial antigen 2 (NG2). By using PDGFRβ or SM22Cre-mediated lineage studies, Tang et al. [34] further confirmed that PDGFRβ-expressing, but not SM22-expressing mural cells have adipogenic potential. Rodeheffer et al. [35] further identified that only CD29^hi:CD34⁺ cells in SVF (about 59% cells in SVF) are of significant adipogenic differentiation populations. It is unknown whether mature brown adipocytes are differentiated from CD29^hi:CD34⁺ precursors in SVF. Lee et al. [36] reported that white adipocytes and β3 agonist-induced brown adipocytes in abdominal WAT originated from the PDGFRα:CD34⁺Sca-1⁺ cells [36]. The same group further documented that cold stress rapidly induces de novo brown adipogenesis in classic BAT. Genetic lineage tracing demonstrated that newly generated brown adipocytes are derived from resident PDGFRα progenitors [37]. Additionally, interscapular brown adipocytes may share the same origin with skeletal muscle. Using in vivo fate mapping, Seale et al. [38, 39] reported that brown, but not white adipocytes arise from Myf5⁺ precursors, which was thought to be expressed only in the myogenic lineage. Even though PVAT shares many biochemical and morphological characteristics with classical brown or white adipocytes, it is unknown whether the adipocytes in PVAT are differentiated from precursors in WAT or BAT as described above.

Similar to classical brown adipocytes, beige adipocytes express UCP-1. However, brown and beige adipocytes may have different developmental origins [40]. Genetic deletion of PPAR-γ in vascular smooth muscle cells (VSMCs) using SM22a-Cre knock in tool, unexpectedly showed a phenotype that the adipose tissues in mesenteric region and peri-aortic region are completely undeveloped. However, adipose tissue in gonadal, subcutaneous, interscapular WAT and BAT were intact [41]. This mouse model strongly supports the notion that there are separate development origins for adipose tissues in different anatomic depots. Later, to address the cellular heterogeneity of different adipose tissue types, Long et al. [42] demonstrated the similarities and differences between brown and beige adipocytes in mice by applying translating ribosome affinity purification technology. Consistent with the report by Chang et al. [41], Long et al. [42] documented a smooth muscle-like gene expression signature (Acta2, Tagln, Myh11, Myl9, and Cnn1) in beige adipocytes, but not in interscapular classical brown adipocytes. By exposing Myh11-GFP/tdTomato mice to cold temperature for 2 weeks, which is known to induce browning in WAT, it was demonstrated that beige adipocytes arise from a Myh11⁺ precursor. Additionally, UCP1 positive lipid droplet-containing adipocytes were found in PRDM16-overexpressing mature VSMCs subjected to adipogenic cocktail and followed by treatment with triiodothyronine, rosiglitazone and insulin, indicating that mature VSMCs can give rise to adipocytes with a thermogenic gene-expression signature [42]. Whereas the above studies [41, 42] suggest that VSMCs might be the origin of some thermogenic adipocytes in PVAT or WAT, further studies are needed to clarify whether thermogenic adipocytes arise from SM22a⁺ or Myh11⁺ mature VSMCs or SMC-like stem cells. Therefore, these reports indicate that PVAT is distinct from the adipose tissues at other locations since the different origins.

As research focusing on PVAT characteristics was largely ignored until 2001, accumulating evidence suggests that PVAT is an active component of the blood vessel wall and contributes to vascular homeostasis by producing a number of biologically active molecules including adipokines (e.g. leptin, adiponectin, omentin, visfatin, resistin, apelin), cytokines/chemokines (e.g. interleukin-6, IL-6; tumor necrosis factor-α, TNF-α; monocyte chemoattractant protein-1, MCP-1), gaseous molecules (e.g. nitric oxide, NO, and hydrogen sulfide, H₂S), prostacyclin, angiotensin-1 to 7 (Ang 1–7), Ang II, methyl palmitate, and reactive oxygen species (ROS) [20, 43‐45]. Thus, PVAT-derived bioactive factors coordinately contribute to vascular tone regulations. PVAT-derived relaxing factors (PVRF) such as adiponectin, NO, H₂S, prostacyclin, angiotensin1-7 and methyl palmitate can promote vasodilation by targeting the medial and the endothelial layer of blood vessels, whereas the PVAT-derived contractile factors (PVCF) such as Ang II, ROS and other unidentified factors may induce blood vessel constriction [46]. Therefore, PVAT is actively involved in the regulation of blood pressure. Circadian rhythm is one of the major physiological regulators of blood pressure, and is controlled by suprachiasmatic nucleus (SCN) where the circadian clock genes are coordinately expressed according to the light cycles. Recently, it was reported that circadian clock genes are expressed in PVAT which transcriptionally control local production of Ang II, suggesting that PVAT is involved in circadian regulation of blood pressure. Nevertheless, it remains unknown whether production of other PVRFs and PVCFs is also controlled in a circadian manner [47].

Atherosclerosis is a progressive chronic metabolic disorder which is characterized by endothelial dysfunction, lipid deposition and inflammation infiltration [48]. It is well-accepted that shear stress-induced endothelial dysfunction/damage is the initial step of the atherosclerosis development. Accordingly, atherosclerotic plaques are most frequently found at the bifurcation sites of the aorta/arteries [49]. Findings indicating that adhesions of circulatory inflammatory cells to the dysfunctional endothelium trigger cholesterol accumulation in the artery wall support the “inside to outside” theory of atherosclerosis development [50]. The atherosclerotic plaque is initiated and progressed in the neointima layer with intact internal elastic lamina, and the plaques are barely found in the media and adventitia layers [51]. However, the function of the endothelium of blood vessels is gradually deteriorating during the obesity process. Quesada et al. demonstrated that PVAT‐derived inflammatory mediators may adversely influence atherosclerotic plaque formation and stability [52]. Interestingly, PVAT also has been shown a protective role in endothelial dysfunction hypercholesterolemic LDL receptor deficient mice, suggesting that PVAT-derived factors might be involved in the regulation of endothelial function [53]. Thus, PVAT might actively influence atherosclerosis development in an “outside to inside” manner.

Adipocyte derived adipokines can modulate several physiological functions including food intake, glucose and lipid metabolism, thermogenesis, neuroendocrine function, blood pressure, and immunity [79]. Dysfunctional adipocytes under overweight/obesity conditions contribute to unbalanced release of adipokines which has been suggested as a potential link between PVAT and atherosclerosis. Atherosclerosis progression is tightly orchestrated by endothelial function, cholesterol transport, inflammation, immune response and VSMCs proliferation, all are intimately associated with adipokines (summarized in Table 1). Adiponectin is known to protect against atherosclerosis development. Adiponectin can suppress the generation of ROS [80], down-regulate the expression of adhesion molecules [81], and inhibit apoptosis [82]. Moreover, recent evidence emphasized that adiponectin is a negative modulator of innate immune response and can down-regulate the release of pro-inflammatory factors, TLR4 expression [83], promote cholesterol efflux from macrophage [84], and polarization of macrophages towards M2 phenotype [85]. Consistently, as an (AMP-activated protein kinase) AMPK agonist, adiponectin has anti-atherogenic properties [86‐89]. In addition, vaspin, apelin and omentin-1 exert protective effects on atherosclerosis by inhibiting ROS generation, enhancing cholesterol efflux and reducing activation of inflammatory macrophages, respectively [90‐92]. Unlike adiponectin, detrimental adipokines such as leptin, chemerin and resistin have been associated with endothelial cell proliferation, angiogenesis, ROS generation and adhesion molecules expression [93‐95]. Particularly, leptin was shown to promote macrophage infiltration, VSMCs proliferation and release of TNF-α and IL-6 [96, 97]. Also, resistin facilitates macrophage recruitment in adipose tissue and atherosclerotic plaque [98], while leukocyte recruitment was shown to correlate with chemerin [99]. Clinical evidence indicating unbalanced adipokine profile (decreased serum adiponectin, apelin, omentin-1 levels and increased serum leptin, resistin, chemerin concentrations) in coronary atherosclerosis disease patients [100‐105], further highlight the importance of adipokines as biomarkers for atherosclerosis.

Adipokines released by PVAT include adiponectin [106], leptin [107], resistin [108], visfatin [109], chemerin [110], lipocalin-2 (LCN2) [58], fatty acid binding protein (FABP) [111], which show direct evidence of PVAT-derived adipokines have effects on the progression of atherosclerosis. Accumulating evidence demonstrates a potential role of PVAT-derived adipokines in atherosclerosis. PVAT-derived adiponectin was shown to inhibit atherosclerosis by promoting macrophage autophagy via the Akt/FOXO3 signaling pathway [64] and to improve NO production by activating eNOS via PI3/Akt phosphorylation [112]. In contrast, PVAT-derived leptin promotes VSMC to undergo a switch into a synthetic phenotype via a p38 MAPK-dependent pathway which can be inhibited by leptin antagonist [107]. Leptin released by PVAT has also been shown to exacerbate coronary endothelial dysfunction through the protein kinase C-beta pathway [113]. Three newly discovered adipokines: visfatin, LCN-2, FABP represent a further link between adipose tissue and atherosclerosis due to their ability to activate macrophages and regulate their phenotypes [114‐116]. Visfatin has been demonstrated to be secreted by PVAT and stimulate VSMCs proliferation in a dose- and time-dependent manner via extracellular signal-regulated kinase (ERK) 1/2 and p38 MAPK signaling pathways [109]. FABP4 locally produced by perivascular fat increased gene expression of inflammatory markers in a dose-dependent manner and was an independent predictor of the severity of coronary stenosis [111]. Nevertheless, further studies are warranted to show whether PVAT could secret all of those adipokines shown in Table 1 which have multiple functions during atherosclerosis process.

Taking together, under physiological condition, PVAT exerts anti-atherogenic effects partly through reducing inflammation, which are largely mediated by protective adipokines, such as adiponectin. However, in the setting of obesity in which inflammatory adipokines, such as leptin, are increased, the protective actions of PVAT are diminished. Thus, the balance between pro- and anti-inflammatory adipokines secreted from adipocytes determines the effects of PVAT on vascular remodeling processes.

Numerous reports support the key role of the inflammatory response in atherosclerosis development [117]. Leukocyte recruitment and pro-inflammatory cytokines participate pivotally in the early phase of atherogenesis. It is now well accepted that dysfunctional adipose tissue in conditions of obesity is a critical source of inflammatory factors that impact the cardiovascular system and promote atherosclerosis. In dysfunctional adipose tissue, secretion of adiponectin is reduced, whereas secretion of pro-inflammatory cytokines is increased, leading to enhanced local inflammation and substantially affecting cardiovascular function and morphology. Whereas earlier studies on inflammation in atherosclerosis have focused on neo-intima and atherosclerotic plaques, it is becoming clear that the inflammatory response in the pathogenesis of atherosclerosis not only occurs in the luminal side of the vessels, but also in the adventitial side [118]. A recent study demonstrated that PVAT and adventitial inflammation precede endothelial dysfunction and atherosclerotic plaque formation [119]. Interestingly, growing evidence suggests that macrophage infiltration is more pronounced in the adventitia than in the intima in animal models, making PVAT inflammation a critical player in atherosclerotic development [120, 121].

PVAT adipocytes and immune cells release vasoactive molecules such as adiponectin and IL-10 which have anti-inflammation effect under physiological conditions [83, 122]. Also, microarray analysis of perimesenteric adipocytes revealed increased expression of certain anti-inflammatory genes including tumor necrosis factor α-induced protein 6 (TAIP6) and suppressor of cytokine signaling 2 (SOCS2) [123]. On the other hand, transplantation of PVAT on the carotid artery resulted in increased vascular remodeling after wire-induced adventitial inflammation and angiogenesis in LDLR knockout animals [70]. Like other adipose depots, PVAT expands and become dysfunctional, then infiltrated with inflammation under pathological conditions [124‐126]. Initiation of inflammation in PVAT results in enhanced secretion of chemokines and cytokines, such as MCP-1 which recruits cells, monocytes and macrophages. Immune cells derived IL-6 and TNF-α induce endothelium damage and increased expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), consequently triggering atherosclerosis development [127, 128]. Importantly, the direct contact of PVAT with the vessels enables significant anti- or pro-inflammatory signaling, mediated by immune cells, adipokines, chemokines and cytokines, that play key roles in atherosclerosis development.

Pathological studies have revealed a defined series of changes in the vessel wall during atherogenesis including endothelial dysfunction, inflammatory cells infiltration, foam cell formation, lipid overload, SMCs migration and proliferation and fibrous plaque formation. PVAT releases biologically active molecules and secretes adiopokines/cytokines that can modulate pathophysiological process of atherosclerosis [20]. The possible role of PVAT in the initiation and progression of atherosclerosis is detailed below.

It is worth mentioning that atherosclerosis is closely associated with and accelerated by metabolic syndrome, especially diabetes. Because the metabolic syndrome occurs in most people with type 2 diabetes, its presence likely accounts for most of the increased incidence of CVD in type 2 diabetes [192]. Furthermore, the presence of diabetes increases the risk of CVD beyond that with metabolic syndrome alone distinguishes it from metabolic syndrome [192]. Oxidative stress, inflammation and IR are key players in the development of atherosclerosis, diabetes and their complications. IR is a major feature of type 2 diabetes and develops in multiple organs, including skeletal muscle, liver, adipose tissue, and heart. Clinical hyperglycemia is always preceded by many years of IR which is associated with obesity [193]. Indeed, a substantial proportion of diabetic patients are obese [194]. Adipose tissue is main sources of free fatty acid (FFA) and pro-inflammatory molecules [195]. Hypertrophy of adipose tissue release abundant FFA binding TLRs to phosphorylation of insulin receptor substrate-1 (IRS-1), result in the down-regulation of the glucose transporter-4 (GLUT-4) and, hence, IR [196, 197]. Phosphorylated IRS-1 alters its ability to activate downstream PI3-kinase and Akt leads to eNOS inhibition and decreased NO production [196]. Furthermore, intracellular oxidation of stored FFA generates ROS leading to vascular inflammation, advanced glycation end products (AGEs) synthesis and protein kinase C (PKC) activation [198, 199]. The initial trigger vascular function in diabetes is the hyperglycemia related reduced NO bioavailability and accumulation of ROS, leading to endothelial dysfunction [200]. Actually, overproduction of ROS by mitochondria is the causal link between high glucose concentration and biochemical pathways of vascular complications in diabetes. Indeed, hyperglycemia-induced ROS production triggers several cellular mechanisms including AGEs sythesis, PKC activation, and NF-κB-mediated inflammation [199, 201]. PKC and its downstream targets play a major role in vascular dysfunction. PKC not only trigger eNOS upcoupling [202‐204] but also increase synthesis of endothelin-1 favouring vasoconstriction and platelet aggregation [205]. Moreover, accumulation of superoxide anion also triggers up-regulation of pro-inflammatory genes MCP-1, VCAM-1, and ICAM-1 via activation of NF-κB signaling [199]. More interesting, glucose intolerance is related with down-regulated PPAR-γ in adipose tissue which impairs development of PVAT and enhances atherosclerosis [184, 206]. Nonetheless, hyperglycemia and IR alone may not fully explain the persistent cardiovascular risk burden associated with type 2 diabetes. Exactly, normalization of glycemia does not reduce macrovascular events suggesting that mediators of other risk factors other than glucose significantly participate to increase the residual cardiovascular risk in diabetic patients [207]. In this regard, adipose dysfunction, result in aberrant released adipokines/cytokines, oxidative stress, hypoxia and inflammation may be particular relevant [208]. One study has demonstrated that fed rat with fructose can induce the changes in PVAT fatty acyl composition and oxidative stress biomarkers which are associated with vascular reactivity. The PVAT redox state was also modified by the fructose overload, as shown by a reduced activity of antioxidant enzymes and augmented oxidative stress [209]. It has been proposed that dysfunction of PVAT is associated with reduced glucose transport by reducing muscle perfusion [210].

As clarified above, dysfunctional adipose leads to an altered secretory profile. Adipokines and cytokines are link to IR, oxidative stress, inflammation or immune response [211‐213]. Adiponectin released from PVAT has been reported to affect insulin sensitivity, inflammatory responses, appetite, atherosclerosis [214]. In adiponectin knockout mice, adiponectin deficiency reduced IRS-1-mediated insulin signaling, resulting in severe diet-induced IR [215]. Furthermore, in obese animals, administration of adiponectin has been found to improve insulin sensitivity and to decrease hyperglycemia and the level of fatty acids in the plasma [216, 217]. Enlargement of adipose tissue is accompanied by reduced expression of adiponectin and increased release of pro-inflammatory cytokines such as TNF-α and IL-6 [214]. Whereas, another study has showed a causal relationship between high serum adiponectin levels and increased cardiovascular mortality rate in patients with type 2 diabetes that pointing to an unexpected deleterious action [218]. The intrinsic biological nature underlying deleterious effect is difficult to understand or only to speculate. Whether adiponectin play a role in increasing atherosclerotic processes is a possibility that deserves further, specifically designed studies. Conversely, in another study, leptin expression was increased in the PVAT, leading to inflammation, fibrosis and vascularization, in patients undergoing coronary artery bypass surgery [219]. Moreover, there is a correlation between increases in plasma leptin and IR and cardiac dysfunction in a type 2 diabetes model [220]. The effects of leptin leading to IR may be indirectly mediated by the brain where it activates the sympathetic nervous system [221]. Another adipokine, resistin, has been described to increase TNF-α and IL-6 production [222]. In endothelial cells, resistin has been found to increase VCAM-1 and ICAM-1 expression [223]. Irisin, a new hormone released by adipose tissue may be involved in pro-atherogenic endothelial disturbances that accompany obesity and T2DM [224]. Omentin-1, a novel adipocytokine mainly expressed in visceral adipose tissue, has been found to inhibit the inflammatory response and improve insulin resistance as well as other obesity-related disorders. Recently, circulating and epicardial adipose tissue (EAT)-derived omentin-1 levels were reduced in patients with CAD. Furthermore, omentin-1 expression in patients with CAD was lower in EAT adjacent to coronary stenotic segments than non-stenotic segments. Whether EAT omentin-1 expression associated with local coronary atherosclerosis should be further clarified [225]. Inflammatory cytokines such as TNF-α may be associated with obesity-related IR. In TNF-α deficient obese mice had lower levels of circulating FFA and were protected from the obesity-related reduction in the insulin receptor signaling in muscle and fat tissues [226]. These findings demonstrated that TNF-α is an important mediator of IR in obesity through its effects on several important sites of insulin action. Taken together, adipose tissue is a resource of multiple active molecules that influence the common pathogenesis of atherosclerosis and diabetes. PVAT attracts more attention as its unique location but more direct evidence should be shown to demonstrate its pivotal function in metabolic disease and cardiovascular system.

PVAT plays key tissue-specific roles during the development of atherosclerosis. Under physiological conditions, PVAT is able to store and combust lipids, generate heat and take up fatty acids from the blood. PVAT also releases multiple vasoactive molecules such as NO, H₂S and adiponectin, which protect against atherosclerosis development. Under pathophysiological conditions (e.g. obesity, hyperlipidemia and diabetes), PVAT becomes dysfunctional. Together with reduced thermogenic capacity due to whitening of BAT-like PVAT, dysfunctional PVAT releases pro-inflammatory adipokines that promote endothelial dysfunction, infiltration of inflammatory cells and migration of VSMC, subsequently promoting atherosclerosis development. Thus, targeting PVAT function is emerging as a novel therapeutic approach for the treatment of atherosclerosis that warrants validation in future research.

In summary, accumulating evidence indicate PVAT as a double-edged sword that possess both anti-atherogenic and pro-atherogenic effects under different conditions. Further study is needed to evaluate whether targeting PVAT function can be used as a novel approach for the treatment of atherosclerosis and subsequent CVD.