Beyond the adventitia: exploring the outer limits of the blood vessel wall.

The anatomy of the arterial wall has traditionally been divided into 3 distinct regions, forming concentric layers surrounding the blood vessel lumen. The intima, consisting of a single layer of endothelial cells in direct contact with the lumen; the media, containing layers of smooth muscle cells and extracellular elastin fibers; and the adventitia, composed largely of collagen and other extracellular matrix protein but also containing fibroblasts, inflammatory cells, and a separate microvasculature. The earliest studies on the role of inflammation in the pathogenesis of atherosclerosis focused on the role of endothelial and smooth muscle cells in disease progression; ie, the cell types that reside within the inner arterial layers.1 Some of the earliest observations demonstrated that that an upregulation of adhesion molecules on the endothelial surface initiates the disease process, resulting in the recruitment of monocytes into the vessel wall. More advanced lesions are characterized by the migration and proliferation of the smooth muscle cells, which further contribute to the remodeling of the arterial microstructure. The accumulation of cells and matrix proteins within the developing plaque leads to a lumen narrowing and an altered intimal microenvironment. The adventitia, on the other hand, has historically been regarded as a minor participant in the disease process, and its functional role in plaque formation and development have largely been overlooked. However, the inflammatory response that occurs in the setting of atherosclerosis clearly involves adventitia. Contributions of adventitia-derived inflammatory cells, cytokines, and microvasculature likely contribute significantly in many different vascular disease states.2,3 The involvement of the adventitia in vascular pathology suggest that there is an “outside-in” component to atherosclerosis that is synergistic with the traditional “inside-out” view of atherogenesis. However, arteries are obviously contained within surrounding tissue which, in the case of most vascular beds, is adipose tissue. If extramedial elements can play a role in cardiovascular disease, what about the involvement of components beyond the adventitia? White adipose tissue (WAT) represents a potentially important and understudied element of vascular inflammation. What was once viewed as an inert reservoir of energy storage is, in actuality, an active and dynamic tissue. The cellular constituents of WAT include the adipocytes, endothelial cells forming the microvasculature, inflammatory cells, and a host of potential stem or progenitor cells. Adipocytes are capable of generating a variety of adipokines,4 and, although WAT as a whole has also been shown to produce a number of inflammatory cytokines,5,6 it is unclear from which cells the cytokines are secreted. The fact that perivascular adipose tissue surrounds many of the arteries that are prone to atherosclerosis suggests an interaction with additional components of the vessel wall. In fact, adipocytes migrating from the perivascular fat have been detected within the adventitia.7 The ability of WAT to promote an inflammatory environment, and the proximity of perivascular adipose tissue to the artery wall raises the possibility that WAT may play a prominent role in vascular pathophysiology. In this issue of Circulation Research, Chatterjee et al8 characterize the gene expression profile of perivascular adipose tissue, demonstrating an unique proinflammatory environment that could potentially influence vascular disease. In this study, the gene expression profile from nondiseased human perivascular adipose tissue samples was compared to samples derived from subcutaneous and visceral depots. Genes indicative of adipocytic differentiation were found to be dramatically lower in perivascular adipose tissue than in subcutaneous and visceral regions, suggesting that perivascular adipocytes exist in a more primitive adipocytic state. This idea was further supported by the morphological appearance of perivascular adipocytes, which were, on average, less than half the diameter of their subcutaneous and visceral counterparts. Interestingly, a comparable reduced state of differentiation was observed in in vitro differentiated preadipocytes derived from the perivascular tissue, but not from preadipocytes isolated from other regions. This suggests that the change in gene expression seen between depots was exclusively attributable to phenotypic differences in adipocytes and not the contributions of other, potentially confounding cell types. It was further observed that inflammatory gene expression was significantly higher in perivascular adipose tissue, a result that was again corroborated by the in vitro differentiation assay. Antiinflammatory adipokines, on the other hand, were markedly reduced. The authors then explored this same phenomenon in a simple but elegant mouse model. As was seen in humans, gene expression in perivascular adipose tissue showed a reduced state of adipocytic differentiation and a heightened inflammatory environment. After just 2 weeks of a high-fat diet, the perivascular adipose tissue appeared to take on an The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From Wallace H. Coulter Department of Biomedical Engineering (S.T.R., W.R.T.), Georgia Institute of Technology and Emory University; and Division of Cardiology, Department of Medicine (W.R.T.), Emory University and the Atlanta Veterans Affairs Medical Center Atlanta, Ga. Correspondence to W. Robert Taylor, MD, PhD, Emory University School of Medicine, Cardiology Division, 1639 Pierce Dr, Suite 319 WMB, Atlanta, GA 30322. E-mail [email protected] (Circ Res. 2009;104:416-418.) © 2009 American Heart Association, Inc.