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Cell Biology International (2012) 36, 327–330 (Printed in Great Britain)
Adipoparacrinology – vascular periadventitial adipose tissue (tunica adiposa) as an example
George N Chaldakov*1, Jerzy Beltowsky†, Peter I Ghenev‡, Marco Fiore§, Plamen Panayotov‖, Gorana Ranči觶 and Luigi Aloe§
*Laboratory of Cell Biology, Medical University, Varna, Bulgaria, †Department of Pathophysiology, Medical University, Lublin, Poland, ‡Department of General and Clinical Pathology, Medical University, Varna, Bulgaria, §Institute of Neurobiology and Molecular Medicine, National Research Council CNR, Rome, Italy, ‖Cardiovascular Surgery Clinic, University St. Marina Hospital, Varna, Bulgaria, and ¶Department of Histology and Embryology, Medical Faculty, University of Ni, Ni, Serbia

Human adipose tissue is partitioned into two large depots (subcutaneous and visceral), and many small depots associated with internal organs, e.g. heart, blood vessels, major lymph nodes, pancreas, prostate gland and ovaries. Since the adipose ‘Big Bang’ led to the discovery of leptin (Zhang, Proenca, Maffei, Barone, Leopold and Friedman, Nature 1994;372:425–32), adipose tissue has been seen not merely as a lipid store, but as a secretory – endocrine and paracrine – organ, particularly in the pathogenesis of a number of diseases. Accordingly, two major sub-fields of adipobiology have emerged, viz. adipoendocrinology and adipoparacrinology, the latter herein being illustrated by PAAT (periadventitial adipose tissue) in vascular walls. A long-standing paradigm holds that the vascular wall consists of three coats, tunica intima, tunica media and tunica adventitia. It is now imperative that ‘to further elucidate vascular function, we should no longer, as hitherto, separate adventitia and PAAT from the vascular wall, but keep them attached and in place, and subject to thorough examination’ (Chaldakov, Fiore, Ghenev, Stankulov and Aloe, Int Med J 2000;7:43–9; Chaldakov, Stankulov and Aloe, Atherosclerosis 2001;154:237–8; Chaldakov GN, Stankulov IS, Fiore M, Ghenev PI and Aloe L, Atherosclerosis 2001;159:57–66). From the available data, we propose that it is time to rethink about vascular wall composition, and suggest that the PAAT may be considered the fourth and outermost vascular coat, hence, tunica adiposa (regarding the proximal segment of coronary artery, it is the innermost part of the EAT (epicardial adipose tissue) situated around the coronary adventitia). Its significance in the pathogenesis and therapy of CMDs (cardiometabolic diseases), particularly atherosclerosis and hypertension, requires further basic, translational and clinical studies.

Key words: adipobiology, adipokines, adipose tissue, cardiometabolic disease, vascular wall

Abbreviations: BMI, body mass index, CMD, cardiometabolic disease, EAT, epicardial adipose tissue, PAAT, periadventitial adipose tissue

1To whom correspondence should be addressed (email

Dedicated to the memory of our friend, Dr Ivan S. Stankulov (1944–2007).

1. Introduction

In 1983, at the Department of Anatomy, University of Chicago Medical School, Chicago, IL, USA, one of us (G.N.C.) presented data on the ultrastructure of fibroblast-like secretion by vascular smooth muscle cells, a key cell type in atherogenesis (reviewed in Chaldakov and Vankov, 1986; Ross, 1999). The question as to whether adventitial fibroblasts may migrate into the intima was raised, to which the answer was given ‘I do not know. It seems impossible.’ However, what seemed ‘impossible’ in 1983 was proven possible by Shi et al. (1996) (also see Wilcox and Scott, 1996; Van der Loo and Martin, 1997). We also proposed that ‘if signals and cells can be translocated from the adventitia into the intima, and hence lead to intimal lesions, then why should we not look for similar reactions from the artery-associated adipose tissue?’ (Chaldakov et al., 2000, 2001a, 2001c).

Recently, obesity and related CMDs (cardiometabolic diseases), such as atherosclerosis, hypertension, Type 2 diabetes and the metabolic syndrome, are globally among the major physical, social and economic burdens. The World Health Organization has predicted a ‘globesity epidemic’ with over one billion adults being overweight [BMI (body mass index)>25 kg/m2] and at least 400 million of these being clinically obese (BMI>30 kg/m2). Arguably, more has been learned about the molecular control of food intake and energy homoeostasis, particularly the role played by adipose tissue in the pathogenesis of various diseases, including CMD (Chaldakov et al., 2000, 2003, 2010a, 2010b; Gualillo et al., 2007; Renes et al., 2009; Trayhurn et al., 2009; Britton and Fox, 2011; Meijer et al., 2011; Bays, 2011; Lu et al., 2011; Matsuzawa et al., 2011). Atherogenic processes, including inflammation, endothelial dysfunction, smooth muscle cell proliferation and insulin resistance, are influenced by adipose tissue-secreted signalling proteins, collectively termed ‘adipokines’ (Table 1). Cumulatively, such an adipocentric approach has integrated (i) the traditional cardiovascular risks (age, sex, smoking, hypertension, dyslipidaemia and homocysteinaemia) and (ii) the accumulation of adipose tissue, including PAAT (periadventitial adipose tissue), into (iii) the global cardiometabolic risk (see Chaldakov et al., 2010a).

Table 1 A selected list of adipose-derived mediators, as related to CMDs

Note that all the components of the renin-angiotensin system are also expressed in PAAT, suggesting their paracrine involvement in CMDs, particularly, atherosclerosis and hypertension. BDNF, brain-derived neurotrophic factor; CRP, C-reactive protein; CXCL8, CXC chemokine ligand 8; H2S, hydrogen sulfide; IL, interleukin; MIP-1 (CCL2), monocyte chemoattractant protein MIP-1 (cysteine–cysteine motif chemokine ligand 2); NGF, nerve growth factor; NO, nitric oxide; RANTES, regulated on activated normal T-cell expressed and secreted; PAI-1, plasminogen activator inhibitor 1; TNFα, tumour necrosis factor α.

Type of mediator Protein
Anti-inflammatory and metabotrophic adipokines Adiponectin, IL-1 receptor antagonist, IL-10, metallothioneins, NGF, BDNF, adrenomedullin, angiopoietin-like protein 4
Pro-inflammatory adipokines Leptin, IL-1, IL-6, IL-17, IL-18, IL-33, TNFα, CRP, MIP-1 (CCL2), IL-8/CXCL8, RANTES, fractalkine (CX3CL1), angiotensin II, chemerin, visfatin, orosomucoid, homocysteine
Vasodilators Adipocyte-derived relaxing factor, NO, H2S, adiponectin, cardiac natriuretic peptide, adrenomedullin
Vasoconstrictors Superoxide anion, angiotensin II, endothelin-1
Haemostatic factors PAI-1, tissue factor

2. The road less traveled…’ (Frost, 1916)

The prevailing response-to-injury hypothesis of Ross (1999) states that atherosclerosis is an inflammatory disease, leading to intimal lesions and luminal loss, i.e. the intimal road to atherogenesis. Accordingly, intima-media thickness became an accepted measure of structural vascular remodelling and a strong predictor of cardiovascular disease. However, it is unlikely that such a road could solely be responsible for the whole multiplex network as that seen in atherogenesis. An interactive approach targeting all structural components of the vascular wall, including PAAT, is required (Chaldakov et al., 2000, 2010a, 2010b; Gollasch and Dubrovska, 2004; Yudkin et al., 2005; Yang and Montani, 2007; Takaoka et al., 2009; Lu et al.; 2010; Ouwens et al., 2010; Wojcicka et al., 2011; Verhagen and Visseren, 2011).

Large- and medium-sized blood vessels in which atherosclerosis usually develop are surrounded by PAAT. Hence, adipokines, by paracrine means, may contribute to different pro- and anti-atherogenic events (Chaldakov et al., 2000, 2010a, 2010b; Gualillo et al., 2007; Trayhurn et al., 2009; Spiroglou et al., 2010; Britton and Fox, 2011; Meijer et al., 2011; Bays, 2011; Lu et al., 2011). This is the essence of adipoparacrinology of cardiovascular disease, particularly, atherosclerosis. Given the key role of inflammation in the development of atherosclerotic lesions, what role might PAAT play in the process of atherogenesis and related disorders? It is known, for instance, that the proximal segments of coronary arteries are surrounded by EAT (epicardial adipose tissue), and these segments are atherosclerosis-prone compared with the distal intramyocardial, adiposa-free segments that are atherosclerosis-resistant (Chaldakov et al., 2000, 2001a, 2001b; Britton and Fox, 2011; Meijer et al., 2011; Bays, 2011; Sacks et al., 2011). However, the removal of PAAT enhances neointima formation after injury, which is attenuated by transplantation of subcutaneous adipose tissue (Takaoka et al., 2009). Likewise, high-fat feeding induces inflammation and decreases adiponectin expression in PAAT, resulting in neointima formation, which is inhibited by local application of adiponectin (Takaoka et al., 2009; also see Matsuzawa et al., 2011).

Consequently, PAAT was conceptualized as the fourth and outermost coat of the vascular wall, hence the term ‘tunica adiposa’ (Figure 1) (Chaldakov et al., 2010b). Therefore, not only intima/media but also adiposa thickness should be measured in identifying, e.g. a high-risk population susceptible to CMD (Louise et al., 1998; Schlett et al., 2009; Skilton et al., 2009). Regarding the coronary artery, EAT also includes pericoronary adipose tissue, i.e. coronary PAAT, thus suggesting its significance in the pathogenesis of coronary atherosclerosis (Chaldakov et al., 2000, 2001a, 2001b; de Feyter, 2011; Hirata et al., 2011). Pharmacological studies aimed at modifying the production and/or receptor sensitivity of adiposa-derived adipokines are required (Töre et al., 2007; Aghamohammadzabeh et al., 2011; Payne et al., 2012).

Overall, the traditional concept of atherogenesis focuses on the intimal road, where ‘inside-out’ inflammatory processes and endothelial dysfunction trigger atherosclerotic plaque formation. Here, we have taken the adipose road, which is less travelled (Frost, 1916), focusing on the possible paracrine role of the tunica adiposa in an ‘outside-in’ signalling pathway in atherosclerosis and related CMD. Note that such an ‘outside-in’ paradigm may also be applied to (i) coronary artery bypass surgery, for example, using ‘no-touch-harvested’ technique of saphenous vein and internal thoracic artery (Dashwood et al., 2011) and (ii) drug application on PAAT surface.

3. Conclusion

Until recently, physicians have looked upon obesity as the accumulation of external adipose tissue. This was routinely seen by various anthropometic measurements, including BMI and waist, hip and – more recently – neck circumference. However, recent non-invasive techniques, such as echography, computed tomography, MRI and positron emission tomography, have revealed a new scenario of adipose distribution and amount, termed ‘adipotopography’ (Rančič et al., 2007) or ‘fat mapping’ (Thomas et al., 2012). We should therefore appreciate not only anthropometric values of external adipose tissue, but more importantly the ‘weight’ of internal adipose tissue, including PAAT/tunica adiposa. TOFI (thin outside, fat inside) and other phenotypes of adipose tissue distribution are given in Table 2. A predictive message of adipoparacrinology is that ‘being thin does not automatically mean you are not fat’, to quote Dr Jimmy Bell, Head of the Molecular Imaging Group at Hammersmith Hospital, London, UK, and master of fat mapping (Louise et al. 1998; Thomas et al., 2012).

Table 2 Adipotopography (fat mapping): variations

The number of asterisks indicates the quality of cardiometabolic health, as related to adipose tissue distribution. Hence, stay TOTI. From Rančič et al. (2007).

Phenotype Definition
TOFI** Thin outside, fat inside
TOTI***** Thin outside, thin inside
FOFI* Fat outside, fat inside
FOTI** Fat outside, thin inside

These may indeed be steps forward, but not the whole journey in the adipoparacrinology of disease. Other examples include (i) retro-orbital adipose tissue and thyroid ophthalmopathy, (ii) mesenteric adipose tissue and Crohn's disease, along with ulcerative colitis, (iii) periprostatic adipose tissue, prostatic cancer and benign prostatic hyperplasia and (iv) mammary gland-associated adipose tissue and breast cancer.


We thank Dr Vladimir Jakovljevic (University of Kragujevac, Kragujevac, Serbia), Dr Harold Sacks (UCLA, Los Angeles, CA, U.S.A.) and Dr Stoyan Stoev (Department of Forensic Medicine, Sofia, Bulgaria) for discussions relating to cardiovascular adipobiology. We apologize to the authors of many relevant articles that were not quoted here for reason of brevity.


Work in the author's laboratories was funded by the National Research Council (CNR), Rome, Italy and the Bulgarian Society for Cell Biology.


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Received 25 July 2011/6 October 2011; accepted 12 December 2011

Published as Cell Biology International Immediate Publication 12 December 2011, doi:10.1042/CBI20110422

© The Author(s) Journal compilation © 2012 Portland Press Limited

ISSN Print: 1065-6995
ISSN Electronic: 1095-8355
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