ABSTRACT Obesity is associated with an increased cardiovascular risk, but the mechanisms underlying the link between increased body weight and vascular disease are incompletely understood.

Over the past 15 years, perivascular adipose tissue has emerged as active component of the vessel wall involved in vascular homeostasis. However, perivascular adipose tissue can adopt

detrimental properties under the influence of obesity and other factors and contribute actively to the pathophysiology of cardiovascular disease. Conversely, changes of the vessel wall may

negatively affect perivascular adipose tissue qualities. In this review, we will discuss the recent literature on the possible direct and indirect connections between perivascular fat

contribution of local fat depots to vascular dysfunction, neointima formation or atherosclerosis. We will briefly highlight results from human and murine genome, miRNome and proteome-wide

expression analyses of potential candidate mediators involved in its paracrine activities and present data on how the cardiovascular risk factors obesity, age or diabetes, but also the

preventive measures weight loss or exercise impact on perivascular expression patterns. A better understanding of this unique adipose tissue depot, its properties and regulatory mechanisms,

may create opportunities for novel diagnostic and therapeutic strategies to combat the cardiovascular consequences of increased body weight. Access through your institution Buy or subscribe

This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access

$259.00 per year only $21.58 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are

calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THE

EVOLVING FUNCTIONS OF THE VASCULATURE IN REGULATING ADIPOSE TISSUE BIOLOGY IN HEALTH AND OBESITY Article 25 September 2023 BEIGING OF PERIVASCULAR ADIPOSE TISSUE REGULATES ITS INFLAMMATION

AND VASCULAR REMODELING Article Open access 07 September 2022 PERIVASCULAR MESENCHYMAL CELLS CONTROL ADIPOSE-TISSUE MACROPHAGE ACCRUAL IN OBESITY Article 02 November 2020 REFERENCES *

Iacobellis G, Ribaudo MC, Assael F, Vecci E, Tiberti C, Zappaterreno A _et al_. Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic

syndrome: a new indicator of cardiovascular risk. _J Clin Endocrinol Metab_ 2003; 88: 5163–5168. Article  CAS  PubMed  Google Scholar  * de Vos AM, Prokop M, Roos CJ, Meijs MF, van der

Schouw YT, Rutten A _et al_. Peri-coronary epicardial adipose tissue is related to cardiovascular risk factors and coronary artery calcification in post-menopausal women. _Eur Heart J_ 2008;

29: 777–783. Article  PubMed  Google Scholar  * Sarin S, Wenger C, Marwaha A, Qureshi A, Go BD, Woomert CA _et al_. Clinical significance of epicardial fat measured using cardiac multislice

computed tomography. _Am J Cardiol_ 2008; 102: 767–771. Article  PubMed  Google Scholar  * Rosito GA, Massaro JM, Hoffmann U, Ruberg FL, Mahabadi AA, Vasan RS _et al_. Pericardial fat,

visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample: the Framingham Heart Study. _Circulation_ 2008; 117: 605–613. Article 

PubMed  Google Scholar  * Saura D, Oliva MJ, Rodriguez D, Pascual-Figal DA, Hurtado JA, Pinar E _et al_. Reproducibility of echocardiographic measurements of epicardial fat thickness. _Int J

Cardiol_ 2010; 141: 311–313. Article  PubMed  Google Scholar  * Gorter PM, de Vos AM, van der Graaf Y, Stella PR, Doevendans PA, Meijs MF _et al_. Relation of epicardial and pericoronary

fat to coronary atherosclerosis and coronary artery calcium in patients undergoing coronary angiography. _Am J Cardiol_ 2008; 102: 380–385. Article  CAS  PubMed  Google Scholar  * Britton

KA, Pedley A, Massaro JM, Corsini EM, Murabito JM, Hoffmann U _et al_. Prevalence, distribution, and risk factor correlates of high thoracic periaortic fat in the Framingham Heart Study. _J

Am Heart Assoc_ 2012; 1: e004200. Article  PubMed  PubMed Central  Google Scholar  * Schlett CL, Massaro JM, Lehman SJ, Bamberg F, O'Donnell CJ, Fox CS _et al_. Novel measurements of

periaortic adipose tissue in comparison to anthropometric measures of obesity, and abdominal adipose tissue. _Int J Obes_ 2009; 33: 226–232. Article  CAS  Google Scholar  * Lehman SJ,

Massaro JM, Schlett CL, O'Donnell CJ, Hoffmann U, Fox CS . Peri-aortic fat, cardiovascular disease risk factors, and aortic calcification: the Framingham Heart Study. _Atherosclerosis_

2010; 210: 656–661. Article  CAS  PubMed  PubMed Central  Google Scholar  * Lakatta EG, Levy D . Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part

II: the aging heart in health: links to heart disease. _Circulation_ 2003; 107: 346–354. Article  PubMed  Google Scholar  * Hubert HB, Feinleib M, McNamara PM, Castelli WP . Obesity as an

independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. _Circulation_ 1983; 67: 968–977. Article  CAS  PubMed  Google Scholar 

* Iacobellis G, Leonetti F . Epicardial adipose tissue and insulin resistance in obese subjects. _J Clin Endocrinol Metab_ 2005; 90: 6300–6302. Article  CAS  PubMed  Google Scholar  *

Konishi M, Sugiyama S, Sugamura K, Nozaki T, Ohba K, Matsubara J _et al_. Association of pericardial fat accumulation rather than abdominal obesity with coronary atherosclerotic plaque

formation in patients with suspected coronary artery disease. _Atherosclerosis_ 2010; 209: 573–578. Article  CAS  PubMed  Google Scholar  * Britton KA, Massaro JM, Murabito JM, Kreger BE,

Hoffmann U, Fox CS . Body fat distribution, incident cardiovascular disease, cancer, and all-cause mortality. _J Am Coll Cardiol_ 2013; 62: 921–925. Article  PubMed  PubMed Central  Google

Scholar  * Pierdomenico SD, Pierdomenico AM, Cuccurullo F, Iacobellis G . Meta-analysis of the relation of echocardiographic epicardial adipose tissue thickness and the metabolic syndrome.

_Am J Cardiol_ 2013; 111: 73–78. Article  PubMed  Google Scholar  * Greif M, Becker A, von Ziegler F, Lebherz C, Lehrke M, Broedl UC _et al_. Pericardial adipose tissue determined by dual

source CT is a risk factor for coronary atherosclerosis. _Arterioscler Thromb Vasc Biol_ 2009; 29: 781–786. Article  CAS  PubMed  Google Scholar  * Tabata M, Kadomatsu T, Fukuhara S, Miyata

K, Ito Y, Endo M _et al_. Angiopoietin-like protein 2 promotes chronic adipose tissue inflammation and obesity-related systemic insulin resistance. _Cell Metab_ 2009; 10: 178–188. Article 

CAS  PubMed  Google Scholar  * Tian Z, Miyata K, Tazume H, Sakaguchi H, Kadomatsu T, Horio E _et al_. Perivascular adipose tissue-secreted angiopoietin-like protein 2 (Angptl2) accelerates

neointimal hyperplasia after endovascular injury. _J Mol Cell Cardiol_ 2013; 57: 1–12. Article  CAS  PubMed  Google Scholar  * Baron AD, Steinberg HO, Chaker H, Leaming R, Johnson A,

Brechtel G . Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans. _J Clin Invest_ 1995; 96: 786–792. Article  CAS  PubMed

  PubMed Central  Google Scholar  * Rittig K, Staib K, Machann J, Bottcher M, Peter A, Schick F _et al_. Perivascular fatty tissue at the brachial artery is linked to insulin resistance but

not to local endothelial dysfunction. _Diabetologia_ 2008; 51: 2093–2099. Article  CAS  PubMed  Google Scholar  * Ruderman NB, Schneider SH, Berchtold P . The ‘metabolically-obese,’

normal-weight individual. _Am J Clin Nutr_ 1981; 34: 1617–1621. Article  CAS  PubMed  Google Scholar  * Ding J, Hsu FC, Harris TB, Liu Y, Kritchevsky SB, Szklo M _et al_. The association of

pericardial fat with incident coronary heart disease: the Multi-Ethnic Study of Atherosclerosis (MESA). _Am J Clin Nutr_ 2009; 90: 499–504. Article  CAS  PubMed  PubMed Central  Google

Scholar  * Shimabukuro M, Hirata Y, Tabata M, Dagvasumberel M, Sato H, Kurobe H _et al_. Epicardial adipose tissue volume and adipocytokine imbalance are strongly linked to human coronary

atherosclerosis. _Arterioscler Thromb Vasc Biol_ 2013; 33: 1077–1084. Article  CAS  PubMed  Google Scholar  * Oka T, Yamamoto H, Ohashi N, Kitagawa T, Kunita E, Utsunomiya H _et al_.

Association between epicardial adipose tissue volume and characteristics of non-calcified plaques assessed by coronary computed tomographic angiography. _Int J Cardiol_ 2012; 161 (1): 45–49.

Article  PubMed  Google Scholar  * Alexopoulos N, McLean DS, Janik M, Arepalli CD, Stillman AE, Raggi P . Epicardial adipose tissue and coronary artery plaque characteristics.

_Atherosclerosis_ 2010; 210: 150–154. Article  CAS  PubMed  Google Scholar  * Gorter PM, van Lindert AS, de Vos AM, Meijs MF, van der Graaf Y, Doevendans PA _et al_. Quantification of

epicardial and peri-coronary fat using cardiac computed tomography; reproducibility and relation with obesity and metabolic syndrome in patients suspected of coronary artery disease.

_Atherosclerosis_ 2008; 197: 896–903. Article  CAS  PubMed  Google Scholar  * Chatterjee TK, Aronow BJ, Tong WS, Manka D, Tang Y, Bogdanov VY _et al_. Human coronary artery perivascular

adipocytes overexpress genes responsible for regulating vascular morphology, inflammation, and hemostasis. _Physiol Genomics_ 2013; 45: 697–709. Article  CAS  PubMed  PubMed Central  Google

Scholar  * Henrichot E, Juge-Aubry CE, Pernin A, Pache JC, Velebit V, Dayer JM _et al_. Production of chemokines by perivascular adipose tissue: a role in the pathogenesis of

atherosclerosis? _Arterioscler Thromb Vasc Biol_ 2005; 25: 2594–2599. Article  CAS  PubMed  Google Scholar  * Mahabadi AA, Reinsch N, Lehmann N, Altenbernd J, Kalsch H, Seibel RM _et al_.

Association of pericoronary fat volume with atherosclerotic plaque burden in the underlying coronary artery: a segment analysis. _Atherosclerosis_ 2010; 211: 195–199. Article  CAS  PubMed 

Google Scholar  * Maurovich-Horvat P, Kallianos K, Engel LC, Szymonifka J, Fox CS, Hoffmann U _et al_. Influence of pericoronary adipose tissue on local coronary atherosclerosis as assessed

by a novel MDCT volumetric method. _Atherosclerosis_ 2011; 219: 151–157. Article  CAS  PubMed  PubMed Central  Google Scholar  * Verhagen SN, Vink A, van der Graaf Y, Visseren FL . Coronary

perivascular adipose tissue characteristics are related to atherosclerotic plaque size and composition. A post-mortem study. _Atherosclerosis_ 2012; 225: 99–104. Article  CAS  PubMed  Google

Scholar  * Park JS, Choi BJ, Choi SY, Yoon MH, Hwang GS, Tahk SJ _et al_. Echocardiographically measured epicardial fat predicts restenosis after coronary stenting. _Scand Cardiovasc J_

2013; 47: 297–302. Article  PubMed  Google Scholar  * Bays HE . Adiposopathy is ‘sick fat’ a cardiovascular disease? _J Am Coll Cardiol_ 2011; 57: 2461–2473. Article  CAS  PubMed  Google

Scholar  * Mazurek T, Zhang L, Zalewski A, Mannion JD, Diehl JT, Arafat H _et al_. Human epicardial adipose tissue is a source of inflammatory mediators. _Circulation_ 2003; 108: 2460–2466.

Article  PubMed  Google Scholar  * Gaborit B, Venteclef N, Ancel P, Pelloux V, Gariboldi V, Leprince P _et al_. Human epicardial adipose tissue has a specific transcriptomic signature

depending on its anatomical peri-atrial, peri-ventricular, or peri-coronary location. _Cardiovasc Res_ 2015; 108: 62–73. Article  CAS  PubMed  Google Scholar  * Vacca M, Di EM, Cariello M,

Graziano G, D'Amore S, Petridis FD _et al_. Integrative miRNA and whole-genome analyses of epicardial adipose tissue in patients with coronary atherosclerosis. _Cardiovasc Res_ 2016;

109: 228–239. Article  CAS  PubMed  Google Scholar  * Salgado-Somoza A, Teijeira-Fernandez E, Fernandez AL, Gonzalez-Juanatey JR, Eiras S . Proteomic analysis of epicardial and subcutaneous

adipose tissue reveals differences in proteins involved in oxidative stress. _Am J Physiol Heart Circ Physiol_ 2010; 299: H202–H209. Article  CAS  PubMed  Google Scholar  * Sacks HS, Fain

JN, Cheema P, Bahouth SW, Garrett E, Wolf RY _et al_. Depot-specific overexpression of proinflammatory, redox, endothelial cell, and angiogenic genes in epicardial fat adjacent to severe

stable coronary atherosclerosis. _Metab Syndr Relat Disord_ 2011; 9: 433–439. Article  CAS  PubMed  Google Scholar  * Chatterjee TK, Stoll LL, Denning GM, Harrelson A, Blomkalns AL, Idelman

G _et al_. Proinflammatory phenotype of perivascular adipocytes: influence of high-fat feeding. _Circ Res_ 2009; 104: 541–549. Article  CAS  PubMed  PubMed Central  Google Scholar  *

Vishvanath L, MacPherson KA, Hepler C, Wang QA, Shao M, Spurgin SB _et al_. Pdgfrbeta+ mural preadipocytes contribute to adipocyte hyperplasia induced by high-fat-diet feeding and prolonged

cold exposure in adult mice. _Cell Metab_ 2016; 23: 350–359. Article  CAS  PubMed  Google Scholar  * Okamoto E, Couse T, De LH, Vinten-Johansen J, Goodman RB, Scott NA _et al_. Perivascular

inflammation after balloon angioplasty of porcine coronary arteries. _Circulation_ 2001; 104: 2228–2235. Article  CAS  PubMed  Google Scholar  * Bot I, de Jager SC, Zernecke A, Lindstedt KA,

van Berkel TJ, Weber C _et al_. Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E-deficient mice. _Circulation_ 2007; 115: 2516–2525.

Article  CAS  PubMed  Google Scholar  * Shi Y, O'Brien JE, Fard A, Mannion JD, Wang D, Zalewski A . Adventitial myofibroblasts contribute to neointimal formation in injured porcine

coronary arteries. _Circulation_ 1996; 94: 1655–1664. Article  CAS  PubMed  Google Scholar  * Verhagen SN, Buijsrogge MP, Vink A, van Herwerden LA, van der Graaf Y, Visseren FL . Secretion

of adipocytokines by perivascular adipose tissue near stenotic and non-stenotic coronary artery segments in patients undergoing CABG. _Atherosclerosis_ 2014; 233: 242–247. Article  CAS 

PubMed  Google Scholar  * Drosos I, Chalikias G, Pavlaki M, Kareli D, Epitropou G, Bougioukas G _et al_. Differences between perivascular adipose tissue surrounding the heart and the

internal mammary artery: possible role for the leptin-inflammation-fibrosis-hypoxia axis. _Clin Res Cardiol_ 2016; 105: 887–900. Article  CAS  PubMed  Google Scholar  * Longchamp A, Tao M,

Bartelt A, Ding K, Lynch L, Hine C _et al_. Surgical injury induces local and distant adipose tissue browning. _Adipocyte_ 2016; 5: 163–174. Article  PubMed  Google Scholar  * Manka D,

Chatterjee TK, Stoll LL, Basford JE, Konaniah ES, Srinivasan R _et al_. Transplanted perivascular adipose tissue accelerates injury-induced neointimal hyperplasia: role of monocyte

chemoattractant protein-1. _Arterioscler Thromb Vasc Biol_ 2014; 34: 1723–1730. Article  CAS  PubMed  PubMed Central  Google Scholar  * Zhang H, Huang Y, Bu D, Chen S, Tang C, Wang G _et

al_. Endogenous sulfur dioxide is a novel adipocyte-derived inflammatory inhibitor. _Sci Rep_ 2016; 6: 27026. Article  CAS  PubMed  PubMed Central  Google Scholar  * Padilla J, Jenkins NT,

Vieira-Potter VJ, Laughlin MH . Divergent phenotype of rat thoracic and abdominal perivascular adipose tissues. _Am J Physiol Regul Integr Comp Physiol_ 2013; 304: R543–R552. Article  CAS 

PubMed  PubMed Central  Google Scholar  * Fleenor BS, Eng JS, Sindler AL, Pham BT, Kloor JD, Seals DR . Superoxide signaling in perivascular adipose tissue promotes age-related artery

stiffness. _Aging Cell_ 2014; 13: 576–578. Article  CAS  PubMed  PubMed Central  Google Scholar  * Barandier C, Montani JP, Yang Z . Mature adipocytes and perivascular adipose tissue

stimulate vascular smooth muscle cell proliferation: effects of aging and obesity. _Am J Physiol Heart Circ Physiol_ 2005; 289: H1807–H1813. Article  CAS  PubMed  Google Scholar  * Soltis

EE, Cassis LA . Influence of perivascular adipose tissue on rat aortic smooth muscle responsiveness. _Clin Exp Hypertens A_ 1991; 13: 277–296. CAS  PubMed  Google Scholar  * Lohn M,

Dubrovska G, Lauterbach B, Luft FC, Gollasch M, Sharma AM . Periadventitial fat releases a vascular relaxing factor. _FASEB J_ 2002; 16: 1057–1063. Article  PubMed  Google Scholar  *

Takemori K, Gao YJ, Ding L, Lu C, Su LY, An WS _et al_. Elevated blood pressure in transgenic lipoatrophic mice and altered vascular function. _Hypertension_ 2007; 49: 365–372. Article  CAS

  PubMed  Google Scholar  * Zou L, Wang W, Liu S, Zhao X, Lyv Y, Du C _et al_. Spontaneous hypertension occurs with adipose tissue dysfunction in perilipin-1 null mice. _Biochim Biophys

Acta_ 2016; 1862: 182–191. Article  CAS  PubMed  Google Scholar  * Ketonen J, Shi J, Martonen E, Mervaala E . Periadventitial adipose tissue promotes endothelial dysfunction via oxidative

stress in diet-induced obese C57Bl/6 mice. _Circ J_ 2010; 74: 1479–1487. Article  CAS  PubMed  Google Scholar  * Galvez B, de CJ, Herold D, Dubrovska G, Arribas S, Gonzalez MC _et al_.

Perivascular adipose tissue and mesenteric vascular function in spontaneously hypertensive rats. _Arterioscler Thromb Vasc Biol_ 2006; 26: 1297–1302. Article  CAS  PubMed  Google Scholar  *

Marchesi C, Ebrahimian T, Angulo O, Paradis P, Schiffrin EL . Endothelial nitric oxide synthase uncoupling and perivascular adipose oxidative stress and inflammation contribute to vascular

dysfunction in a rodent model of metabolic syndrome. _Hypertension_ 2009; 54: 1384–1392. Article  CAS  PubMed  Google Scholar  * Aghamohammadzadeh R, Unwin RD, Greenstein AS, Heagerty AM .

Effects of obesity on perivascular adipose tissue vasorelaxant function: nitric oxide, inflammation and elevated systemic blood pressure. _J Vasc Res_ 2015; 52: 299–305. Article  CAS  PubMed

  Google Scholar  * Xia N, Horke S, Habermeier A, Closs EI, Reifenberg G, Gericke A _et al_. Uncoupling of endothelial nitric oxide synthase in perivascular adipose tissue of diet-induced

obese mice. _Arterioscler Thromb Vasc Biol_ 2016; 36: 78–85. Article  CAS  PubMed  Google Scholar  * Meyer MR, Fredette NC, Barton M, Prossnitz ER . Regulation of vascular smooth muscle tone

by adipose-derived contracting factor. _PLoS One_ 2013; 8: e79245. Article  CAS  PubMed  PubMed Central  Google Scholar  * Owen MK, Witzmann FA, McKenney ML, Lai X, Berwick ZC, Moberly SP

_et al_. Perivascular adipose tissue potentiates contraction of coronary vascular smooth muscle: influence of obesity. _Circulation_ 2013; 128: 9–18. Article  CAS  PubMed  PubMed Central 

Google Scholar  * Withers SB, Agabiti-Rosei C, Livingstone DM, Little MC, Aslam R, Malik RA _et al_. Macrophage activation is responsible for loss of anticontractile function in inflamed

perivascular fat. _Arterioscler Thromb Vasc Biol_ 2011; 31: 908–913. Article  CAS  PubMed  Google Scholar  * Payne GA, Borbouse L, Kumar S, Neeb Z, Alloosh M, Sturek M _et al_. Epicardial

perivascular adipose-derived leptin exacerbates coronary endothelial dysfunction in metabolic syndrome via a protein kinase C-beta pathway. _Arterioscler Thromb Vasc Biol_ 2010; 30:

1711–1717. Article  CAS  PubMed  PubMed Central  Google Scholar  * Mikolajczyk TP, Nosalski R, Szczepaniak P, Budzyn K, Osmenda G, Skiba D _et al_. Role of chemokine RANTES in the regulation

of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension. _FASEB J_ 2016; 30: 1987–1999. Article  CAS  PubMed  PubMed Central  Google Scholar  * Engeli S,

Schling P, Gorzelniak K, Boschmann M, Janke J, Ailhaud G _et al_. The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome? _Int J Biochem Cell Biol_ 2003;

35: 807–825. Article  CAS  PubMed  Google Scholar  * Schroeter MR, Eschholz N, Herzberg S, Jerchel I, Leifheit-Nestler M, Czepluch FS _et al_. Leptin-dependent and leptin-independent

paracrine effects of perivascular adipose tissue on neointima formation. _Arterioscler Thromb Vasc Biol_ 2013; 33: 980–987. Article  CAS  PubMed  Google Scholar  * Watts SW, Dorrance AM,

Penfold ME, Rourke JL, Sinal CJ, Seitz B _et al_. Chemerin connects fat to arterial contraction. _Arterioscler Thromb Vasc Biol_ 2013; 33: 1320–1328. Article  CAS  PubMed  PubMed Central 

Google Scholar  * Takaoka M, Nagata D, Kihara S, Shimomura I, Kimura Y, Tabata Y _et al_. Periadventitial adipose tissue plays a critical role in vascular remodeling. _Circ Res_ 2009; 105:

906–911. Article  CAS  PubMed  Google Scholar  * Karastergiou K, Evans I, Ogston N, Miheisi N, Nair D, Kaski JC _et al_. Epicardial adipokines in obesity and coronary artery disease induce

atherogenic changes in monocytes and endothelial cells. _Arterioscler Thromb Vasc Biol_ 2010; 30: 1340–1346. Article  CAS  PubMed  Google Scholar  * Hou N, Liu Y, Han F, Wang D, Hou X, Hou S

_et al_. Irisin improves perivascular adipose tissue dysfunction via regulation of the heme oxygenase-1/adiponectin axis in diet-induced obese mice. _J Mol Cell Cardiol_ 2016; 99: 188–196.

Article  CAS  PubMed  Google Scholar  * Li H, Wang YP, Zhang LN, Tian G . Perivascular adipose tissue-derived leptin promotes vascular smooth muscle cell phenotypic switching via p38

mitogen-activated protein kinase in metabolic syndrome rats. _Exp Biol Med_ 2014; 239: 954–965. Article  CAS  Google Scholar  * Margaritis M, Antonopoulos AS, Digby J, Lee R, Reilly S,

Coutinho P _et al_. Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in

human vessels. _Circulation_ 2013; 127: 2209–2221. Article  CAS  PubMed  Google Scholar  * Moos MP, John N, Grabner R, Nossmann S, Gunther B, Vollandt R _et al_. The lamina adventitia is the

major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice. _Arterioscler Thromb Vasc Biol_ 2005; 25: 2386–2391. Article  CAS  PubMed  Google Scholar  *

Hagita S, Osaka M, Shimokado K, Yoshida M . Adipose inflammation initiates recruitment of leukocytes to mouse femoral artery: role of adipo-vascular axis in chronic inflammation. _PLoS ONE_

2011; 6: e19871. Article  CAS  PubMed  PubMed Central  Google Scholar  * Ohman MK, Luo W, Wang H, Guo C, Abdallah W, Russo HM _et al_. Perivascular visceral adipose tissue induces

atherosclerosis in apolipoprotein E deficient mice. _Atherosclerosis_ 2011; 219: 33–39. Article  CAS  PubMed  PubMed Central  Google Scholar  * Li C, Wang Z, Wang C, Ma Q, Zhao Y .

Perivascular adipose tissue-derived adiponectin inhibits collar-induced carotid atherosclerosis by promoting macrophage autophagy. _PLoS ONE_ 2015; 10: e0124031. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Irie D, Kawahito H, Wakana N, Kato T, Kishida S, Kikai M _et al_. Transplantation of periaortic adipose tissue from angiotensin receptor blocker-treated mice

markedly ameliorates atherosclerosis development in apoE-/- mice. _J Renin Angiotensin Aldosterone Syst_ 2015; 16: 67–78. Article  CAS  PubMed  Google Scholar  * McKenney ML, Schultz KA,

Boyd JH, Byrd JP, Alloosh M, Teague SD _et al_. Epicardial adipose excision slows the progression of porcine coronary atherosclerosis. _J Cardiothorac Surg_ 2014; 9: 2. Article  PubMed 

PubMed Central  Google Scholar  * Chang L, Villacorta L, Li R, Hamblin M, Xu W, Dou C _et al_. Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-gamma

deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis. _Circulation_ 2012; 126: 1067–1078. Article  CAS  PubMed  PubMed Central  Google Scholar

  * Rittig K, Dolderer JH, Balletshofer B, Machann J, Schick F, Meile T _et al_. The secretion pattern of perivascular fat cells is different from that of subcutaneous and visceral fat

cells. _Diabetologia_ 2012; 55: 1514–1525. Article  CAS  PubMed  Google Scholar  * Wakana N, Irie D, Kikai M, Terada K, Yamamoto K, Kawahito H _et al_. Maternal high-fat diet exaggerates

atherosclerosis in adult offspring by augmenting periaortic adipose tissue-specific proinflammatory response. _Arterioscler Thromb Vasc Biol_ 2015; 35: 558–569. Article  CAS  PubMed  Google

Scholar  * Zaborska KE, Wareing M, Edwards G, Austin C . Loss of anti-contractile effect of perivascular adipose tissue in offspring of obese rats. _Int J Obes_ 2016; 40: 1205–1214. Article

  CAS  Google Scholar  * Iacobellis G, Singh N, Wharton S, Sharma AM . Substantial changes in epicardial fat thickness after weight loss in severely obese subjects. _Obesity_ 2008; 16:

1693–1697. Article  PubMed  Google Scholar  * Aghamohammadzadeh R, Greenstein AS, Yadav R, Jeziorska M, Hama S, Soltani F _et al_. Effects of bariatric surgery on human small artery

function: evidence for reduction in perivascular adipocyte inflammation, and the restoration of normal anticontractile activity despite persistent obesity. _J Am Coll Cardiol_ 2013; 62:

128–135. Article  PubMed  PubMed Central  Google Scholar  * Bussey CE, Withers SB, Aldous RG, Edwards G, Heagerty AM . Obesity-related perivascular adipose tissue damage is reversed by

sustained weight loss in the rat. _Arterioscler Thromb Vasc Biol_ 2016; 36: 1377–1385. Article  CAS  PubMed  Google Scholar  * Reifenberger MS, Turk JR, Newcomer SC, Booth FW, Laughlin MH .

Perivascular fat alters reactivity of coronary artery: effects of diet and exercise. _Med Sci Sports Exerc_ 2007; 39: 2125–2134. Article  CAS  PubMed  PubMed Central  Google Scholar  *

Bunker AK, Laughlin MH . Influence of exercise and perivascular adipose tissue on coronary artery vasomotor function in a familial hypercholesterolemic porcine atherosclerosis model. _J Appl

Physiol_ 2010; 108: 490–497. Article  PubMed  Google Scholar  * Zeng ZH, Zhang ZH, Luo BH, He WK, Liang LY, He CC _et al_. The functional changes of the perivascular adipose tissue in

spontaneously hypertensive rats and the effects of atorvastatin therapy. _Clin Exp Hypertens_ 2009; 31: 355–363. Article  CAS  PubMed  Google Scholar  * Sun X, Hou N, Han F, Guo Y, Hui Z, Du

G _et al_. Effect of high free fatty acids on the anti-contractile response of perivascular adipose tissue in rat aorta. _J Mol Cell Cardiol_ 2013; 63: 169–174. Article  CAS  PubMed  Google

Scholar  * Xia N, Weisenburger S, Koch E, Burkart M, Reifenberg G, Förstermann U _et al_. Restoration of perivascular adipose tissue function in diet-induced obese mice without changing

bodyweight. _Br J Pharmacol_ 2017; e-pub ahead of print 5 January 2017 doi:10.1111/bph.13703. Article  CAS  PubMed  PubMed Central  Google Scholar  * Molenaar EA, Massaro JM, Jacques PF, Pou

KM, Ellison RC, Hoffmann U _et al_. Association of lifestyle factors with abdominal subcutaneous and visceral adiposity: the Framingham Heart Study. _Diabetes Care_ 2009; 32: 505–510.

Article  PubMed  PubMed Central  Google Scholar  * Gao YJ, Holloway AC, Zeng ZH, Lim GE, Petrik JJ, Foster WG _et al_. Prenatal exposure to nicotine causes postnatal obesity and altered

perivascular adipose tissue function. _Obes Res_ 2005; 13: 687–692. Article  PubMed  Google Scholar  * Rossi C, Santini E, Chiarugi M, Salvati A, Comassi M, Vitolo E _et al_. The complex

P2X7 receptor/inflammasome in perivascular fat tissue of heavy smokers. _Eur J Clin Invest_ 2014; 44: 295–302. Article  CAS  PubMed  Google Scholar  * Tao M, Yu P, Nguyen BT, Mizrahi B,

Savion N, Kolodgie FD _et al_. Locally applied leptin induces regional aortic wall degeneration preceding aneurysm formation in apolipoprotein E-deficient mice. _Arterioscler Thromb Vasc

Biol_ 2013; 33: 311–320. Article  CAS  PubMed  Google Scholar  * Gillum MP, Kotas ME, Erion DM, Kursawe R, Chatterjee P, Nead KT _et al_. SirT1 regulates adipose tissue inflammation.

_Diabetes_ 2011; 60: 3235–3245. Article  CAS  PubMed  PubMed Central  Google Scholar  * Virdis A, Duranti E, Rossi C, Dell'Agnello U, Santini E, Anselmino M _et al_. Tumour necrosis

factor-alpha participates on the endothelin-1/nitric oxide imbalance in small arteries from obese patients: role of perivascular adipose tissue. _Eur Heart J_ 2015; 36: 784–794. Article  CAS

  PubMed  Google Scholar  * Cheng KH, Chu CS, Lee KT, Lin TH, Hsieh CC, Chiu CC _et al_. Adipocytokines and proinflammatory mediators from abdominal and epicardial adipose tissue in patients

with coronary artery disease. _Int J Obes_ 2008; 32: 268–274. Article  CAS  Google Scholar  * Langheim S, Dreas L, Veschini L, Maisano F, Foglieni C, Ferrarello S _et al_. Increased

expression and secretion of resistin in epicardial adipose tissue of patients with acute coronary syndrome. _Am J Physiol Heart Circ Physiol_ 2010; 298: H746–H753. Article  PubMed  Google

Scholar  * Lohmann C, Schafer N, von LT, Sokrates Stein MA, Boren J, Rutti S _et al_. Atherosclerotic mice exhibit systemic inflammation in periadventitial and visceral adipose tissue,

liver, and pancreatic islets. _Atherosclerosis_ 2009; 207: 360–367. Article  CAS  PubMed  Google Scholar  * Kawahito H, Yamada H, Irie D, Kato T, Akakabe Y, Kishida S _et al_. Periaortic

adipose tissue-specific activation of the renin-angiotensin system contributes to atherosclerosis development in uninephrectomized apoE-/- mice. _Am J Physiol Heart Circ Physiol_ 2013; 305:

H667–H675. Article  CAS  PubMed  Google Scholar  * Miao CY, Li ZY . The role of perivascular adipose tissue in vascular smooth muscle cell growth. _Br J Pharmacol_ 2012; 165: 643–658.

Article  CAS  PubMed  PubMed Central  Google Scholar  * Gil-Ortega M, Condezo-Hoyos L, Garcia-Prieto CF, Arribas SM, Gonzalez MC, Aranguez I _et al_. Imbalance between pro and anti-oxidant

mechanisms in perivascular adipose tissue aggravates long-term high-fat diet-derived endothelial dysfunction. _PLoS ONE_ 2014; 9: e95312. Article  CAS  PubMed  PubMed Central  Google Scholar

  * Schlich R, Willems M, Greulich S, Ruppe F, Knoefel WT, Ouwens DM _et al_. VEGF in the crosstalk between human adipocytes and smooth muscle cells: depot-specific release from visceral and

perivascular adipose tissue. _Mediators Inflamm_ 2013; 2013: 982458. Article  CAS  PubMed  PubMed Central  Google Scholar  * Ruan CC, Zhu DL, Chen QZ, Chen J, Guo SJ, Li XD _et al_.

Perivascular adipose tissue-derived complement 3 is required for adventitial fibroblast functions and adventitial remodeling in deoxycorticosterone acetate-salt hypertensive rats.

_Arterioscler Thromb Vasc Biol_ 2010; 30: 2568–2574. Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS The authors thank Marina Janocha for expert technical

assistance. This work was supported by a grant from the German Research Foundation (Deutsche Forschungsgemeinschaft; Scha 808/7-1) to KS and by National and European Union funds from the

‘Operational Programme Education and Lifelong Learning (NSRF 2007–2013) MIS 379527’ to SK and KS. The work of SK was supported by the Federal Ministry of Education and Research (BMBF;

01EO1003 and 01EO1503) in Germany. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Center for Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany K Schäfer & I Drosos

* Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany S Konstantinides Authors * K Schäfer View author publications You can also search for this author

inPubMed Google Scholar * I Drosos View author publications You can also search for this author inPubMed Google Scholar * S Konstantinides View author publications You can also search for

this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to K Schäfer. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Schäfer, K., Drosos, I. & Konstantinides, S. Perivascular adipose tissue: epiphenomenon or local risk factor?.

_Int J Obes_ 41, 1311–1323 (2017). https://doi.org/10.1038/ijo.2017.121 Download citation * Received: 03 January 2017 * Revised: 24 April 2017 * Accepted: 01 May 2017 * Published: 22 May

2017 * Issue Date: September 2017 * DOI: https://doi.org/10.1038/ijo.2017.121 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable

link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative