Perivascular adipose tissue and vascular perturbation/atherosclerosis

Abstract

Atherosclerosis is orchestrated by complex interactions between vascular and inflammatory cells. Traditionally, it has been considered to be an intimal inflammatory disease, characterized by endothelial dysfunction, inflammatory cell recruitment, lipid oxidation, and foam cell formation. This “inside-out” signaling paradigm has been accepted as dogma for many years, despite the fact that inflammatory cells are far more prevalent in the adventitia compared with the intima. For decades, the origin of adventitial inflammation in atherosclerosis was unknown. The fact that these inflammatory cells were observed to cluster at the margin of perivascular adipose tissues (PVAT), a unique and highly inflammatory adipose depot that surrounds most atherosclerosis-prone blood vessels, has stimulated interest in PVAT-mediated “outside-in” signaling in vascular pathophysiology, including atherosclerosis. The phenotype of perivascular adipocytes underlies the functional characteristics of this depot, including its role in adventitial inflammatory cell recruitment, trafficking to the intima via the vasa vasorum, and atherosclerosis perturbation. This review is focused on emerging concepts pertaining to “outside-in” signaling in atherosclerosis driven by dysfunctional PVAT during diet-induced obesity, and recent strategies for atherosclerosis prediction and prognostication based upon this hypothesis.

1. Introduction

The prevalence of obesity is increasing worldwide, particularly in the United States and Europe; more than 30% of adults in the United States are obese [body mass index (BMI)>30]. Obesity is closely associated with the pathogenesis of atherosclerosis and other forms of cardiovascular disease (CVD) such as hypertension and coronary artery disease, by multiple mechanisms, including perturbing blood pressure, glucose homeostasis, and lipid metabolism.^1,2,3

Adipose tissues play a fundamental role in energy metabolism, storing and releasing lipids during caloric excess or deprivation. In diet-induced obesity (DIO), expanded adipose tissues become inflamed and dysfunctional, and pro-inflammatory adipocytokines and free fatty acids released by dysfunctional adipose tissues can cause vascular inflammation and oxidative stress, thus augmenting atherosclerosis in a systemic manner.^4,5 Human adipose tissue is anatomically divided into two main subtypes, subcutaneous fat and visceral fat. Adipose tissue is also classified into white adipose tissue (WAT), brown adipose tissue (BAT) and beige adipose tissue based on function, phenotype and morphology. WAT, localized both in visceral and subcutaneous regions, has a large capacity to store energy, whereas BAT has pronounced thermogenic functions. Beige fat, interspersed with WAT, exhibits a brown-like phenotype under cold exposure or pharmacological stimulation. Fat tissue surrounding the heart and great vessels can exhibit features of WAT or BAT, depending on the exact location, species, etc., and understanding the modulatory role of these localized fat depots in cardiovascular disease has attracted much interest. Pericardial and paracardial adipose tissues are located within and outside of the pericardium, respectively. While these depots are not thought to communicate directly with myocardium or coronary arteries, expansion of pericardial adipose tissue during visceral obesity could theoretically impose a mechanical burden on the heart, impeding cardiac efficiency and hampering filling. Epicardial adipose tissue, localized between the myocardium and the visceral layer of the pericardium, is in direct communication with the heart, where it may invade cardiac tissues, regulate metabolism and contribute to arrhythmias such as atrial fibrillation. The component of epicardial adipose tissue that surrounds coronary blood vessels is known as perivascular adipose tissue (PVAT) surrounds most blood vessels except the cerebral vasculature, and directly communicates with adjacent blood vessels through adipocytokine release to regulate vascular function.⁶ PVAT surrounding large vessels is contiguous with the adventitial layer, whereas perivascular adipocytes in small vessels and microvessels are an integral part of the vascular wall itself.⁷ Importantly, PVAT expands in obesity and is capable of responding to atherogenic stimuli and interacting with inflammatory cells, the nervous system and vascular cells to promote or modulate vascular disease.

The fact that PVAT resides at the outermost portion of the arterial wall implies that it contributes to the pathogenesis of atherosclerosis through an “outside-in” mechanism, which is in contradistinction to the traditional “inside-out” theory of atherosclerosis. Consequently, the vascular biology community has been slow to accept the importance of PVAT in atherosclerosis. Furthermore, PVAT was summarily removed from blood vessels and discarded by most investigators, so the extent of PVAT inflammation in atherosclerosis was not recognized for many years. Interest in the potential role of PVAT in atherosclerosis was largely driven by physiologists who discovered that PVAT releases transferrable factors that regulate vascular function, thus providing proof-of-principle of an outside-in mechanism of operation. Additionally, clinician-researchers observed that atherosclerosis of the coronary tree is anatomically co-localized with PVAT,⁸ which further stimulated research into the biology of this unique adipose depot. Development of enhanced imaging techniques that can quantify PVAT volume and inflammation in patients has accelerated translational research in this area. This brief article discuss key concepts linking PVAT to vascular perturbation, with an emphasis on the pathogenesis of atherosclerosis; those seeking more detailed information about the biology of PVAT are referred to comprehensive review articles.

2. General concepts and functions of PVAT

Understanding how PVAT may perturb the vasculature/atherosclerosis requires a general familiarity with its gross structure and cellular components. PVAT is juxtaposed to the vascular adventitia and devoid of an anatomical barrier, which permits it to directly communicate with vascular cells, such as adventitial fibroblasts, vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). Adipocytokines secreted from PVAT can readily gain access to the vascular wall and promote either vasoconstriction or vasodilation via paracrine activities. In physiological conditions, PVAT plays a fundamental role in vasodilation via production of adipokines, including adiponectin, omentin and adipocyte-derived relaxing factor (ADRF). Under inflammatory states, such as obesity, vasodilatory adipokine release is diminished from inflamed, dysfunctional PVAT, thus promoting vasoconstriction.

PVAT consists of different cell types, (e.g. mature adipocytes, preadipocytes, mesenchymal stem cells, immune cells), and these cells interact by transferring signaling molecules such as adipocytokines and non-coding RNAs. Immune cells infiltrating PVAT in obesity can promote vasoconstriction, endothelial dysfunction and VSMC proliferation via crosstalk with vascular cells. Leptin released from adipocytes can stimulate macrophages to produce pro-inflammatory cytokines [e.g. tumor necrosis factor (TNF)-α, interferon (IFN)-γ],⁹ and RANTES produced by adipocytes also enhances CD3⁺ T cell recruitment into PVAT,¹⁰ suggesting that crosstalk between immune cells and adipocytes is an important feature driving PVAT inflammation.

The developmental origin of PVAT remains to be fully elucidated. It has been suggested that adipocytes in different adipose tissues originate from distinct precursor cell lineages. White adipocytes may develop from platelet-derived growth factor (PDGF) α-expressing progenitor cells, while brown adipocytes may derive from myogenic progenitor cells.¹¹ Neural crest cells were recently reported to differentiate into brown adipocytes and form periaortic arch adipose tissue.¹² Chang et al. demonstrated that VSMC-specific gene deletion of peroxisome proliferator-activated receptor (PPAR)-γ, a master regulator of adipogenesis, resulted in the complete loss of PVAT, but not WAT or BAT, indicating that PVAT may originate from VSMC lineage.^13,14 This is also supported by data that human adipocytes from subcutaneous adipose tissue and pericoronary PVAT exhibit distinct gene expression patterns related to both early development and vascular functions.²⁵ However, further studies are required to fully understand the origins of perivascular adipocytes.

3. Classical view of atherosclerosis: an intimal inflammatory disease (“inside-out” theory)

Traditionally, endothelial injury and dysfunction has been considered to underlie atherosclerosis development through “inside-out” signaling that triggers vascular inflammation and lipid uptake.¹⁵ EC dysfunction can be caused by a variety of factors, including perturbed shear stress, hyperlipoproteinemia, and reactive oxygen species (ROS) generated by cigarette smoking and the NADPH oxidase (NOX) system in EC and VSMC. This leads to reduced bioavailability of nitric oxide (NO), which plays a key role in regulating vascular tone and thrombosis. Increased production of 4-hydroxynonenal (4-HNE, a lipid hydroperoxide end product) also promotes EC and VSMC dysfunction. In addition, vasoprotective prostacyclin (PGI₂) production is reduced in dysfunctional EC. EC dysfunction in turn promotes a cascade of inflammatory cell recruitment via intracellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expression, lipid uptake, foam cell formation, and atherosclerotic lesion formation. Inflamed human blood vessels release pro-inflammatory cytokines such as TNFα, interleukin (IL)-6 and IFNγ, which can translocate into the perivascular region and induce PVAT inflammation.¹⁶ Collectively, these findings support the traditional “inside-out” theory of atherosclerosis (Figure), which proposes that the intima is the “soil” for atherosclerosis and restenosis.¹⁷

“Inside-out” vs “outside-in” signaling in the pathogenesis of atherosclerosis.

EC-mediated “inside-out” signaling triggers vascular inflammation via ROS production and ICAM-1/VCAM-1 expression to promote atherosclerotic lesion formation. Elevated oxidative stress can increase 4-HNE production which promotes EC and VSMC dysfunction, while 4-HNE released from healthy vascular wall increases adiponectin production from PVAT. On the other hand, PVAT-mediated “outside-in” signaling through pro-inflammatory adipocytokines (e.g. leptin, MCP-1, TNFα) produced by adipocytes and immune cells also contributes to atherosclerosis development. EC; endothelial cell, 4-HNE; 4-hydroxynonenal, ICAM-1; intracellular adhesion molecule 1, MCP-1; monocyte chemoattractant protein 1, NOX; NADPH oxidase, PVAT; perivascular adipose tissue, ROS: reactive oxygen species, TNFα; tumor necrosis factor α, VCAM-1; vascular cell adhesion molecule 1, VSMC; vascular smooth muscle cell.

4. The adventitia in atherosclerosis: potential association with PVAT (“outside-in” theory)

Classical studies examining inflammation in atherosclerotic blood vessels understandably focused primarily on intimal lesions. Inflammation of the adventitia in atherosclerosis has, however, been recognized for many years.¹⁸ In 1915, Albutt et al. identified significant numbers of inflammatory cells in the adventitia surrounding atherosclerotic arteries.¹⁹ Subsequently, Schwartz and Mitchell in 1962 examined over 440 tissue blocks from 111 randomly selected humans and reported a positive correlation between the level of adventitial inflammation and the severity of atherosclerosis.²⁰ More recently, arterial balloon injury was observed to rapidly induce adventitial inflammation in pigs, and this inflammation extended into the PVAT, suggesting that inflammation present in the outer layers of the arterial wall could result from a pathological process instigated at the intima.²¹ Similar findings were subsequently reported in a mouse model of arterial injury.²² Furthermore, Henrichot et al. demonstrated enhanced inflammation in PVAT surrounding atherosclerotic human blood vessels.²³ Dense clusters of CD68⁺ macrophages and CD3⁺ T cells were detected in PVAT close to the adventitial margin of the atherosclerotic aorta; the numbers of inflammatory cells in PVAT diminished towards the periphery of the adipose tissue depot, suggesting that inflammation could have passively spread from the adventitia into PVAT. Collectively, these observations are consistent with the “inside-out” theory of atherosclerosis and support the concept that inflamed adventitia and PVAT may emanate from intimal disease and thus serve as a marker, rather than a mediator, of atherosclerosis.

Conversely, Pagano et al. identified a constitutively active NOX system in the adventitia that functions as a powerful oxidant generator to perturb vascular function.²⁴ Superoxide produced by NOX in adventitial fibroblasts was demonstrated to inactivate NO, thus promoting vascular endothelial dysfunction and vasoconstriction. In addition to ROS, fibroblasts also produce endothelin-1, a potent vasoconstrictor,²⁵ further suggesting an important role for adventitial-derived paracrine factors in perturbing vascular function. These observations provided proof-of-principle that factors produced by the outer layers of the blood vessel wall can significantly impact the inner layers in an “outside-in” manner. Moreover, Moos et al. compared the numbers of inflammatory cells in adventitia versus intima in hyperlipidemic apolipoprotein E (ApoE) knockout (KO) mice.²⁶ Remarkably, they detected up to 80-fold more CD3⁺ T cells in the adventitia as compared to the intima of aged ApoE KO mice. Furthermore, the T cells (mainly CD3⁺/CD4⁺ cells) appeared to form clusters with B lymphoid follicle-like structures that resemble tertiary follicles; fully developed follicles contained various types of adaptive immune cells, including antigen-presenting CD11c⁺/MHCII⁺ dendritic cells, proliferating B cells (B220⁺/Ki67⁺) and antibody-producing CD138⁺ plasma cells. This seminal report placed the outer layers of the arterial wall squarely in the crosshairs of vascular immunologists and paved the way for studies linking PVAT to vascular inflammation and atherosclerosis.

In 2009, Chatterjee et al. performed a detailed investigation into the phenotype of human perivascular adipocytes.²⁷ Importantly, the tissues/cells examined in this study came from healthy individuals without pre-existing cardiovascular disease. Human pericoronary perivascular adipocytes were observed to produce more pro-inflammatory cytokines than adipocytes from other depots, including the omentum. The amount of monocyte chemoattractant protein (MCP)-1 produced by the pericoronary adipocytes was approximately 50-fold higher than that produced by subcutaneous or visceral adipocytes isolated from the same individuals. Moreover, short-term high fat diet (HFD) feeding in mice for 2 weeks dramatically perturbed periaortic adipose tissues in mice, downregulating anti-inflammatory adiponectin and upregulating pro-inflammatory MIP-1α, while having little effect on other adipose depots. These findings suggested that PVAT is primed to promote vascular disease in an “outside-in” manner.

Subsequent studies support that PVAT is a key mediator of adventitial inflammation and proliferation.^{19, 21, 22} Zhang et al. reported that PDGF-D specifically expressed in perivascular adipocytes plays a critical role in adventitial inflammation and fibroblast proliferation/migration.²⁸ Using a balloon-injury carotid model, Zhu et al. demonstrated that obese mini pigs (Chinese Bama miniature pigs)²⁹ exhibited increased adventitial inflammation, fibroblast proliferation/migration, and PVAT dysfunction (e.g. macrophage accumulation, increased expression of leptin and IL-1β, and decreased levels of adiponectin) compared to normal mini pigs in response to vascular injury.³⁰ Interestingly, adventitial fibroblasts cultured with PVAT-conditioned medium from obese mini pigs exhibited enhanced proliferation attributed to PVAT-derived IL-1. Additionally, extracellular vesicles secreted from perivascular adipocytes were reported to regulate vascular inflammation. Li et al. showed that in mice fed a HFD for 16 weeks, PVAT-derived extracellular vesicles evoked inflammatory responses in PVAT and transferred microRNAs (e.g. miR-221–3p) to the medial layer to promote VSMC proliferation.³¹ These data suggest that obesity-induced PVAT dysfunction can promote adventitial inflammation and vascular remodeling.

The vasa vasorum, a microvessel network originating from adventitial arteries, plays a primary role in supplying nutrients and oxygen to the vessel wall. In atherosclerotic arteries, the vasa vasorum proliferates, which has been attributed to vascular hypoxia imposed by intimal thickening, thus creating a diffusion barrier for oxygen.³² In such case, one would expect that vasa vasorum proliferation would only be seen in the later stages of atherosclerosis. Yet, in HFD fed pigs, vasa vasorum proliferation was detected early, well before the development of intimal thickening and even preceding the onset of endothelial dysfunction.³³ This finding suggests that factors other than intimal hypoxia promote vasa vasorum proliferation in atherosclerosis, and mounting evidence suggests that dysfunctional PVAT may be responsible.^34,35 In addition to promoting intraplaque hemorrhage, the proliferative vasa vasorum may serve as a conduit for inflammatory cell trafficking between the PVAT and neointima, thus illustrating the complex interplay between the inner and outermost layers of the vascular wall. Taken together, these findings suggest that PVAT-mediated “outside-in” signaling plays a prominent contributory role in the pathogenesis of atherosclerosis, in harmony with classical EC-derived “inside-out” signaling (Figure).

5. Phenotypic differences of PVAT in rodents and humans

Mounting evidence suggests that PVAT can be either white- or brown-like tissue, and that function and phenotype of PVAT differs depending on the species, anatomical location and vascular bed. Rodent abdominal PVAT exhibits characteristics of both WAT and BAT based on metabolic features and gene expression, but thoracic PVAT is more similar to BAT compared to abdominal PVAT.³⁶ PVAT surrounding other vessels such as the carotid, mesenteric and femoral artery is more like WAT. In rodents, abdominal PVAT is highly responsive to HFD and becomes more white-like, whereas thoracic PVAT is relatively resistant to these changes.³⁸ While brown-like PVAT plays an important role in non-shivering thermogenesis, anti-inflammation and vascular homeostasis, growing data suggest that “whitening” of PVAT induced by HFD can result in metabolic and vascular disease such as diabetes and atherosclerosis.³⁷ Interestingly, PVAT whitening in mice can be reversed by cold exposure³⁸. In addition, β-adrenergic stimulation increases lipolysis and activates thermogenesis in WAT, and adrenoreceptors are also present in PVAT,³⁹ suggesting that PVAT “re-browning” could be an important therapeutic target for metabolic and vascular disease. Also, PVAT browning and brown adipocyte differentiation of PVAT-resident progenitor cells is impaired with aging in rodents, possibly related to reduced miR-146b-3p expression.⁴⁰ However, mechanisms of PVAT whitening and re-browning are not fully understood, particularly in humans.

As compared to rodent PVAT, brown-like phenotypes are rare in human PVAT, and PVAT found in most human blood vessels is similar to WAT.⁴¹ In lean healthy human subjects, chronic cold exposure can induce “browning” of thoracic PVAT in association with increased energy expenditure, but the impact on body weight appears to be minimal.⁴² These divergent features of rodent versus humans PVAT suggest that more research is needed to understand the mechanistic bases for these differences, and that caution should be exercised when extrapolating functions of PVAT between mice and humans.

6. Atheroprotective versus pro-atherogenic role of PVAT

As mentioned above, healthy PVAT has anti-contractile and vasoprotective properties that are mediated by release of anti-inflammatory adipokines such as ADRF, adiponectin and omentin. Adiponectin produced by healthy PVAT was reported to promote BH4-mediated endothelial nitric oxide synthase (eNOS) function, while adiponectin expression was found to be induced by 4-HNE released from vascular wall.⁴³ Under some conditions, selective deletion of PVAT in mice can lead to impaired EC function and augmented atherosclerosis,³¹ suggesting a protective role of healthy PVAT. Also, certain immune cells residing in healthy PVAT, such as B-1 cells, may ameliorate macrophage-derived pro-inflammatory cytokine production and protect against atherosclerosis.⁴⁴ However, directly testing the role of PVAT in modulating vascular disease is challenging, and all models developed thus far have limitations. A number of groups have transplanted adipose tissues to the vascular wall to study the local effects of PVAT, but the majority of these studies employed subcutaneous or visceral fat, rather than authentic PVAT. Terada et al. transplanted thoracic PVAT harvested from wild-type mice onto the abdominal aorta of ApoE knockout mice and observed reduced atherosclerosis attributed to increased transforming growth factor (TGF)-β1 signaling.⁴⁵ However, these protective effects of PVAT were likely related to brown-like functions, which is of limited relevance to humans.

On the other hand, dysfunctional PVAT plays a central role in adventitial inflammation, which has been suggested to be an important aspect of atherosclerotic development. Manka et al. showed that transplantation of small amount (2–3 mg) of white PVAT, but not subcutaneous adipose tissue, from HFD-fed wild-type mice to low density lipoprotein receptor (LDLR) KO mice significantly augmented carotid adventitial inflammation, angiogenesis and wire injury-induced neointima formation,²⁶ indicating a unique pathogenic role of white PVAT. Furthermore, MCP-1 expression was found to be increased by 6-fold in PVAT of HFD-fed mice, and gene deletion of MCP-1 in transplanted PVAT prevented enhanced adventitial angiogenesis and neointima formation, suggesting a pathogenic role for PVAT-derived MCP-1 on the vasculature. Furthermore, differentiated human perivascular adipocytes exhibited greater angiogenic potential as compared with subcutaneous and perirenal adipocytes derived from the same patients.²⁵ These data support the notion that PVAT could be a key mediator of both intimal disease and vasa vasorum proliferation.

The potent effects of transplanted white PVAT observed in the latter study raised the possibility that expansion of PVAT in obesity could potentially impact atherosclerosis in a systemic manner. Indeed, Horimatsu et al. demonstrated that transplantation of 50 mg of white PVAT isolated from HFD-fed wild-type mice onto the abdominal aorta of LDLR KO mice promoted endothelial dysfunction and atherosclerosis in the remote thoracic aorta, which was independent of body weight, adiposity, lipid levels and insulin sensitivity.⁴⁶ Transplantation of the same amounts (50 mg) of subcutaneous or visceral (epididymal) adipose tissue did not have such effects, again pointing to the unique pathogenic role of PVAT in obesity. The transplanted PVAT was examined at the termination of the study and exhibited a heightened inflammatory state as compared to subcutaneous and epididymal adipose tissue controls, but whether this contributed to the remote endothelial dysfunction or atherosclerosis remains to be determined. Nevertheless, these findings support the notion that PVAT may be an important contributor to atherosclerosis in the obesity era.

7. New perspective: imaging PVAT as a barometer of intimal inflammation and predictor of atherosclerotic events in humans

Whether PVAT is a marker, modulator and/or mediator of vascular disease remains an ongoing debate. Meanwhile, newer imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), are emerging as powerful tools to detect PVAT inflammation in humans. In particular, the CT fat attenuation index (FAI), an imaging metric of water-to-lipid ratio, was demonstrated to correlate with adipocyte size and lipid content in PVAT with excellent sensitivity and specificity.⁴⁷ Vascular inflammation is associated with diminished adipogenic differentiation and enhanced lipolysis in PVAT, which together reduce lipid content, thus resulting in a more positive perivascular FAI.⁵¹. In the latter study, the FAI gradient in PVAT surrounding coronary arteries of 273 patients was able to discern regions with vulnerable atherosclerotic plaques, and validation studies suggest that monitoring PVAT by CT imaging approach may be a promising non-invasive clinical strategy for predicting CVD events.^48,49 In addition, CT imaging has been employed to monitor coronary perivascular inflammation in vasospastic angina patients.⁵⁰ Finally, treatment with immunosuppressive agents has been demonstrated to improve the FAI in PVAT, suggesting that vascular inflammation in PVAT may be reversible, and that imaging PVAT might be a useful surrogate endpoint in future atherosclerosis studies in humans.⁴⁶

8. Conclusions

Until recently, outside-in signaling via PVAT has received little attention by the vascular biology community. With the onset of the obesity epidemic, expansion of dysfunctional PVAT has not only called attention to the potential importance of this unique adipose depot in atherosclerosis but it is also helping to illuminate mechanisms whereby obesity promotes cardiovascular disease. Under some conditions, PVAT can play a homeostatic role to favorably modulate vascular function and inflammation. However, in obesity, PVAT-produced adipocytokines contribute significantly to adventitial inflammation, neovascularization (e.g., vasa vasorum proliferation), and neointima formation. While PVAT transplantation is increasingly being employed in mouse models, few studies have used authentic PVAT. Moreover, the PVAT phenotypic differences between mice and humans suggest that caution should be exercised when extrapolating data between the two species. Studies of PVAT biology in humans are advancing rapidly, guided by CT technology, and suggest that techniques such as FAI may enable us to monitor vascular inflammation and predict atherosclerotic events in patients.

Highlights.

• Understanding of pathogenesis of atherosclerosis in the obesity era may be evolving from “inside-out” to “outside-in” via PVAT signaling.

• PVAT in humans is mostly white adipose tissue, while in rodents, it is a mixture of brown and white; the functional differences may help to explain pro-atherogenic vs atheroprotective effects.

• PVAT becomes inflamed in obesity and may promote angiogenesis/vasa vasorum proliferation to augment vascular disease.

• Imaging of PVAT in humans is feasible and predictive of atherosclerotic events and prognosis.

Abbreviations

ADRF

adipocyte-derived relaxing factor

ApoE

apolipoprotein E

BAT

brown adipose tissue

CT

computed tomography

CVD

cardiovascular disease

DIO

diet-induced obesity

EC

endothelial cell

eNOS

endothelial nitric oxide synthase

HFD

high fat diet

HNE

hydroxynonenal

IFN

interferon

IL

interleukin

KO

knockout

LDL

low density lipoprotein

LDLR

low density lipoprotein receptor

MCP-1

monocyte chemoattractant protein 1

MRI

magnetic resonance imaging

NO

nitric oxide

NOX

NADPH oxidase

PDGF

platelet-derived growth factor

PPAR

peroxisome proliferator-activated receptor

PVAT

perivascular adipose tissue

ROS

reactive oxygen species

TNF

tumor necrosis factor

TGF

transforming growth factor

VSMC

vascular smooth muscle cell

WAT

white adipose tissue