Tunica Arterial Adventitia: A New Exploration in Intimal Hyperplasia

The adventitia of the arterial wall has been long recognized as a more collagen-rich supportive connective tissue compared to its adjacent structures, the intima and media. However, more data show that this definition is far too limiting. Experimental data have unambiguously shown that many kinds of arterial injury (i.e., arterial endothelial injury, vein bypass grafting) induce not only a variety of pathological changes in intima and media, but also adventitial remodeling [1-3]. It has also been reported that the adventitia’s injury response is involved in intimal and medial restructuring [4]. The purpose of this brief review is to highlight the recent findings on the role of the adventitia in vascular injury responses.


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The adventitia of the arterial wall has been long recognized as a more collagen-rich supportive connective tissue compared to its adjacent structures, the intima and media. However, more data show that this definition is far too limiting. Experimental data have unambiguously shown that many kinds of arterial injury (i.e., arterial endothelial injury, vein bypass grafting) induce not only a variety of pathological changes in intima and media, but also adventitial remodeling [1][2][3]. It has also been reported that the adventitia's injury response is involved in intimal and medial restructuring [4]. The purpose of this brief review is to highlight the recent findings on the role of the adventitia in vascular injury responses.

Normal Structure of Arterial Wall
Arterial walls have traditionally been divided into three distinct concentric layers surrounding the vessel lumen: intima, media, and adventitia. The tunica intima consists of a single layer of endothelial cells (ECs) in direct contact with blood flow. This tightly junctional monolayer of ECs rests on extracellular matrix components including collagen type IV, and heparin sulfate proteoglycans.5 The tunica media, consisting of layers of smooth muscle cells (SMCs), extracellular elastin fiber, and other matrix components, is responsible for the muscular construction of blood vessels. The tunica adventitia is mainly composed of collagens and other extracellular matrix proteins, but also contains fibroblasts, adipocytes, vasa vasorum, rare macrophages, and some perivascular nerves [1,5,6].

Re-examing the Roles of Adventitia
For decades, vascular biology research has focused on the EC, SMC, and extracellular matrix (in tunica media) in vessel function and injury response [7]. However; other cellular components within the adventitia have also been implicated in these processes. Indeed, other than collagen and proteoglycans, the adventitial site of most arteries also has a substantial layer of adipocytes and fibroblasts adjacent to smooth muscle layer. The population of cells residing in the vascular adventitia was initially thought to be relatively static and passive, with only structurally supportive and anatomically protective roles [8]. Recent evidence, however, suggests dynamic roles: both vascular fibroblasts and perivascular adipocytes are actively involved in the control of vascular SMC activation, phenotype switch, and perhaps vascular growth [7]. In addition, further evidence implies that the adult adventitia harbors progenitor cell populations that display multilineage differentiation potential and play various roles in arterial injury response [9][10][11][12]. However, despite these exciting discoveries reported in recent years by several laboratories, how these components interact to achieve a complex and integrated control of vascular tone remains an underexplored area in vascular biology research. Various investigators at the cutting edge of the field demonstrated that these cells spontaneously differentiate into adventitial pericytes, and can be differentiated into various vascular cells (endothelial and smooth muscle cells). In addition, these progenitor cells possess a crucial paracrine capacity and, thus, can maintain arterial homeostasis and respond to injury [13].

Adventitia and Intimal Hyperplasia
Under normal conditions, the mature arterial wall has a low to undetectable proliferation rate of ECs and SMCs. Once subjected to injury, however, all three layers demonstrate significantly increased proliferative ability. Many reported results have suggested that the proliferation and migration of medial SMCs promote the aggregation of neointimal cells that highly express SMC markers. Therefore, it has been believed that medial SMCs play a vital role in neointimal formation [14][15][16] Nevertheless, in the past decade, this view was greatly challenged by studies that transplanted extrinsic cells into adventitia or labeled intrinsic adventitial cells to investigate their roles in response to vessel injury [17][18][19][20]. Those studies indicated that the resident adventitial cells are able to migrate into the neointima and contribute to intimal hyperplasia following injury. Based on the results of many studies which have shown phenotypic transformation of adventitial fibroblasts to SMC-like myofibroblasts, those cells are thought to play a pivotal role in the vessel injury response [20,21]. Additionally, some recent studies found that adventitial progenitor cells and adipocytes may participate in neointimal formation and vascular remodeling after injury [10,22]. Accumulating evidence has shown that the adventitia functioning as progenitor cell niche maintains arterial wall integrity [11,[23][24][25].

Journal of Vascular Medicine & Surgery
Experimental evidence has elaborated a direct role of adventitial cells in mediating vascular tone. Fibroblasts and macrophages in adventitia can produce nitric oxide in response to injury, in turn affecting vessel contraction and vessel remodeling [26]. However, how adventitial cells sense injury and consequently initiate the remodeling in an "outsidein" manner remains unclear. Likewise, the crosstalk between adventitia and intima or media is not entirely understood. Although sympathetic nerve terminals in adventitia are found to diffuse into media and induce SMC contraction, cell or neuron signaling involved in this process requires more thorough investigation.1 Therefore, the study of the adventitia will further elucidate its role within vascular biology.

Summary
We expect that more questions will be put forth with increased studies of the adventitial layer of arterial wall. Investigating these questions will provide a better understanding on how various vascular cellular components interact each other to maintain and restore vessel functions.