Cell Biol. Int. (2012) 36, 327–330 (Printed in Great Britain)
Commentary
Adipoparacrinology – vascular periadventitial adipose tissue (tunica adiposa) as an example George N. Chaldakov1*, Jerzy Beltowsky{, Peter I. Ghenev{, Marco Fiore1, Plamen PanayotovI, Gorana Rancˇicˇ1," and Luigi Aloe1 * 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 1 Institute of Neurobiology and Molecular Medicine, National Research Council (CNR), Rome, Italy I Cardiovascular Surgery Clinic, University St. Marina Hospital, Varna, Bulgaria " Department of Histology and Embryology, Medical Faculty, University of Nisˇ, Nisˇ, Serbia {
Abstract 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. Keywords: adipobiology; adipokines; adipose tissue; cardiometabolic disease; vascular wall
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).
1
To whom correspondence should be addressed (email
[email protected]). Dedicated to the memory of our friend, Dr Ivan S. Stankulov (1944–2007). Abbreviations: BMI, body mass index; CMD, cardiometabolic disease; EAT, epicardial adipose tissue; PAAT, periadventitial adipose tissue.
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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; TNFa, tumour necrosis factor a. Type of mediator Anti-inflammatory and metabotrophic adipokines Pro-inflammatory adipokines Vasodilators Vasoconstrictors Haemostatic factors
Protein Adiponectin, IL-1 receptor antagonist, IL-10, metallothioneins, NGF, BDNF, adrenomedullin, angiopoietin-like protein 4 Leptin, IL-1, IL-6, IL-17, IL-18, IL-33, TNFa, CRP, MIP-1 (CCL2), IL-8/CXCL8, RANTES, fractalkine (CX3CL1), angiotensin II, chemerin, visfatin, orosomucoid, homocysteine Adipocyte-derived relaxing factor, NO, H2S, adiponectin, cardiac natriuretic peptide, adrenomedullin Superoxide anion, angiotensin II, endothelin-1 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 antiatherogenic 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
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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 (To¨re 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-touchharvested’ technique of saphenous vein and internal thoracic artery (Dashwood et al., 2011) and (ii) drug application on PAAT surface.
Figure 1
Schematic presentation of vascular wall composed of 4 tissue coats (tunicae intima, media, adventitia and adipose) Arrows show that tunica media is a target of 2 vasorelaxing factors, endotheliumderived relaxing factor (EDRF) and adipose-derived relaxing factor (ADRF). From Chaldakov et al. (2010b) with permission E2010 Editrice Kurtis.
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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 Rancˇicˇ et al. (2007). Phenotype TOFI** TOTI***** FOFI* FOTI**
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’ (Rancˇicˇ 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). 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 glandassociated adipose tissue and breast cancer.
Acknowledgements 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.
Funding Work in the author’s laboratories was funded by the National Research Council (CNR), Rome, Italy and the Bulgarian Society for Cell Biology.
References Aghamohammadzabeh R, Withers SB, Lynch FM, Greenstein AS, Malik R, Heagerty AM. Perivascular adipose tissue from human systemic and coronary vessels: the emergence of a new
E The Author(s) Journal compilation E 2012 Portland Press Limited
Definition Thin outside, fat inside Thin outside, thin inside Fat outside, fat inside Fat outside, thin inside
pharmacotherapeutic target. Br J Pharmacol 2011;doi:10.1111/j. 1476-5381.2011.01479.x. Bays HE. Adiposopathy is ‘sick fat’ a cardiovascular disease? J Am Coll Cardiol 2011;57:2461–73. Britton KA, Fox CS. Perivascular adipose tissue and vascular disease. Clin Lipidol 2011;6:79–91. Chaldakov GN, Vankov VN. Morphological aspects of secretion in the arterial smooth muscle cell, with special reference to the Golgi complex and microtubular cytoskeleton. Atherosclerosis 1986;61:175–92 Chaldakov GN, Fiore M, Ghenev PI, Stankulov IS, Aloe L. Atherosclerotic lesions: possible interactive involvement of intima, adventitia and associated adipose tissue. Int Med J 2000;7:43–9. Chaldakov GN, Stankulov IS, Aloe L. Subepicardial adipose tissue in human coronary atherosclerosis: another neglected phenomenon. Atherosclerosis 2001a;154:237–8. Chaldakov GN, Stankulov IS, Fiore M, Ghenev PI, Aloe L. Nerve growth factor levels and mast cell distribution in human coronary atherosclerosis. Atherosclerosis 2001b;159:57–66. Chaldakov GN, Stankulov IS, Fiore M, Hristova MG, Rancˇic´ G, Ghenev PI et al. Adipoendocrinology and adipoparacrinology: emerging fields of study on the adipose tissue. Biomed Rev 2001c;12:31–9. Chaldakov GN, Stankulov IS, Hristova M, Ghenev PI. Adipobiology of disease: adipokines and adipokine-targeted pharmacology. Curr Pharm Des 2003;9:1023–31. Chaldakov GN, Ghenev PI, Hristova MG, Panayotov P, Aloe L. Perivascular adipose tissue: a novel component of global cardiometabolic risk. CMR eJournal 2010a;3:19–22. Chaldakov GN, Fiore M, Rancic G, Ghenev PI, Tuncel N, Beltowski J et al. Rethinking vascular wall: periadventitial adipose tissue (tunica adiposa). Obesity Metab 2010b;6:46–9. Dashwood MR, Dooley A, Shi-Wen X, Abraham DJ, Dreifaldt M, Souza DS. Perivascular fat-derived leptin: a potential role in improved vein graft performance in coronary artery bypass surgery. Interact Cardiovasc Thorac Surg 2011;12:170–3. de Feyter PJ. Epicardial adipose tissue: an emerging role for the development of coronary atherosclerosis. Clin Cardiol 2011;34:143–4. Frost R. The road not taken. In: Mountain interval. New York, NY: Henry Holt and Company; 1916:‘…two roads diverged in a wood, and I – I took the one less traveled by, And that has made all the difference.’ Gollasch M, Dubrovska G. Paracrine role for periadventitial adipose tissue in the regulation of arterial tone. Trends Pharmacol Sci 2004;25:647–53. Gualillo O, Gonza´lez-Juanatey JR, Lago F. The emerging role of adipokines as mediators of cardiovascular function: physiologic and clinical perspectives. Trends Cardiovasc Med 2007;17:275–83. Hirata Y, Tabata M, Kurobe H, Motoki T, Akaike M, Nishio C et al. Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue. J Am Coll Cardiol 2011;58:248–55. Louise TE, Saeed N, Hajnal JV, Brynes A, Goldstone AP, Frost G, Bell JD. Magnetic resonance imaging of total body fat. J Appl Physiol 1998;85:1778–85. Lu C, Su LY, Lee RM, Gao YJ. Mechanisms for perivascular adipose tissue-mediated potentiation of vascular contraction to perivascular neuronal stimulation: the role of adipocyte-derived angiotensin II. Eur J Pharmacol 2010;634:107–12. Lu C, Su LY, Lee RM, Gao YJ. Alterations in perivascular adipose tissue structure and function in hypertension. Eur J Pharmacol 2011;656:68–73.
Volume 36 (3) N pages 327–330 N www.cellbiolint.org
329
Vascular adipoparacrinology
Matsuzawa Y, Funahashi T, Nakamura T. The concept of metabolic syndrome: contribution of visceral fat accumulation and its molecular mechanism. J Atheroscler Thromb 2011;18:629–39. Meijer RI, Serne EH, Smulders YM, van Hinsbergh VW, Yudkin JS, Eringa EC. Perivascular adipose tissue and its role in type 2 diabetes and cardiovascular disease. Curr Diab Rep 2011;11:211–7. Ouwens DM, Sell H, Greulich S, Eckel J. The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease. J Cell Mol Med 2010;14:2223–34. Payne GA, Kohr MC, Tune JD. Epicardial perivascular adipose tissue as a therapeutic target in obesity-related coronary artery disease. Br J Pharmacol 2012;165:659–69. Rancˇicˇ G, Petrovicˇ A, Sekulovicˇ-Stefanovicˇ L, Bojanicˇ V, Ghenev PI. Adipotopography: TOFI versus TOTI, or a hidden Homo obesus. In: The First International Symposium on Adipobiology and Adipopharmacology, 20 October 2007, Varna, Bulgaria. pp 13–14A. Renes J, Rosenow A, Mariman E. Novel adipocyte features discovered by adipoproteomics. Adipobiology 2009;1:7–18. Ross R. Mechanisms of disease: atherosclerosis – an inflammatory disease. N Engl J Med 1999;340:115–26. 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;9:433–9. 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 (Lond) 2009;33:226–32. Shi Y, O’Brien JE, Fard A, Mannion JD, Wang D, Zalewski A. Adventitial myofibroblasts contribute to neointimat formation in injured porcine coronary arteries. Circulation 1996;94:1655–64. Skilton MR, Se´rusclat A, Sethu AH, Brun S, Bernard S, Balkau B et al. Noninvasive measurement of carotid extra-media thickness: associations with cardiovascular risk factors and intima-media thickness. JACC Cardiovasc Imaging 2009;2:176–82.
Spiroglou SG, Kostopoulos CG, Varakis JN, Papadaki HH. Adipokines in periaortic and epicardial adipose tissue: Differential expression and relation to atherosclerosis. J Atheroscler Thromb 2010;17:115–30. 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;105:906–11. Thomas EL, Parkinson JR, Frost GS, Goldstone AP, Dore´ CJ, McCarthy JP et al. The missing risk: MRI and MRS phenotyping of abdominal adiposity and ectopic fat. Obesity (Silver Spring) 2012;20:76–87. To¨re F, Tonchev AB, Fiore M, Tuncel N, Atanassova P, Aloe L et al. From adipose tissue protein secretion to adipopharmacology of disease. Immunol Endocr Metab Agents Med Chem 2007;7:149–55. Trayhurn P, de Heredia FP, Wang B, de Oliveira C, Gonzalez-Muniesa P, Wood IS. Cellular hypoxia: a key modulator of adipocyte function in obesity? Adipobiology 2009;1:19–26. Van der Loo B, Martin JF. The adventitia, endothelium and atherosclerosis. Int J Microcirc Clin Exp 1997;17:280–8. Vergahen SN, Visseren FLJ. Perivascular adipose tissue as a cause of atherosclerosis. Atherosclerosis 2011;214:3–10. Wilcox JN, Scott NA. Potential role of the adventitia in arteritis and atherosclerosis. Int J Cardiol 1996;54(Suppl.):S21–35. Wojcicka G, Jamroz-Wisniewska A, Attanasova P, Chaldakov GN, Chylinska-Kula B, Beltowski J. Differential effects of statins on endogenous H2S formation in perivascular adipose tissue. Pharmacol Res 2011;63:68–76. Yang Z, Montani JP. Emerging roles of perivascular adipose tissue in regulation of vascular functions. Immun Endocr Metab Agents Med Chem 2007;7:137–41. Yudkin JS, Eringa E, Stehouwer CD. ‘Vasocrine’ signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet 2005;365:1817–20. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425–32.
Received 25 July 2011/ 6 October 2011; accepted 12 December 2011 Published as Immediate Publication 12 December 2011, doi 10.1042/CBI20110422
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