Atherosclerosis is considered an “inside-out” response, that begins with the dysfunction of intimal endothelial cells and leads to neointimal plaque formation. The adventitia of large blood vessels has been recognized as an active part of the vessel wall that is involved in the process of atherosclerosis. There are characteristic changes in the adventitial vasa vasorum that are associated with the development of atheromatous plaques. However, whether vasa vasorum plays a causative or merely reactive role in the atherosclerotic process is not completely clear. Recent studies report that the vascular wall contains a number of stem/progenitor cells that may contribute to vascular remodeling. Microvessels serve as the vascular niche that maintains the resident stem/progenitor cells of the tissue. Therefore, the vasa vasorum may contribute to vascular remodeling through not only its conventional function as a blood conducting tube, but also its new conceptual function as a stem cell reservoir. This brief review highlights the recent advances contributing to our understanding of the role of the adventitial vasa vasorum in the atherosclerosis and discusses new concept that involves vascular-resident factors, the vasa vasorum and its associated vascular-resident stem cells, in the atherosclerotic process.
Atherosclerosis, a chronic progressive inflammatory disease of the arterial wall, has traditionally been considered an “inside-out” response in which injury to intimal endothelial cells initiates the adhesion/invasion of inflammatory cells in the subendothelial space. Subsequently atherosclerotic plaques grow by the accumulation of inflammatory cells and lipid substances and the proliferation of vascular smooth muscle cells [
The adventitia is no longer viewed as a passive support structure in large vessels. The vascular adventitia, which harbors a wide variety of components such as fibroblasts, inflammatory cells, stem/progenitor cells, and vasa vasorum, can act as a biological central processing unit in vessel wall function. Recent emerging evidence proposes a new paradigm regarding the sites/direction of the atherosclerotic process, the “outside-in” hypothesis. Under this paradigm, vascular inflammation is initiated in the adventitia and progresses toward the intima [
A number of studies have demonstrated that the vascular walls act as a perivascular niche for stem/progenitor cells that contribute to vascular repair, fibrosis, and atherosclerosis (Table
Resident progenitor cells within the vasculature.
Location | Name | Selection method | Markers | Comments | Reference |
---|---|---|---|---|---|
Adventitia | Vascular progenitor cells |
|
Sca1+ | Differentiate into |
Hu et al., 2004 [ |
Vascular progenitor cells |
|
CD34+ | |
Campagnolo et al., 2010 [ | |
(Saphenous vein-derived progenitor cells; |
After culture in the presence of serum, CD34 were subsided, and the following markers were increased: | ||||
(CD34+ cKit+ cells were located at perivascular sites of the |
CD29+, CD44+, CD105+, SOX2+, Nestin+, NG2+ (CD146−) | Act as |
|||
Adventitial stem cells |
|
CD34+ | CD34+ CD146− cells display |
| |
CD31−, CD146−, and CD45− | |||||
These cells acquired a | |||||
Adventitial pericyte progenitor cells |
|
NG2+, CD146+, PDGFR+ |
|
Tigges et al., 2013 [ | |
Some of these cells also express CD29+, CD90+ | |||||
NG2/CD146+ cells were increased in the adventitia of the injured vasculature | |||||
|
|||||
Vasculogenic zone | |
|
CD34+, KDR (VEGFR2)+, Tie2+ | |
Zengin et al., 2006 [ |
CD105−, CD144− | |||||
(CD34+ cells located at the “ |
|||||
Angiogenic MSCs | Adherent culture condition (cells were isolated from human thoracic artery, and select the adherent cells forming colony ) | MSC markers (CD44+, CD90+, CD105+, etc.) | Differentiate into |
| |
CD45−, CD146−, vWF− | (These cells were heterogenous) | ||||
(CD34+ cKit+ cells were enriched in the |
It is uncertain whether the isolated cells are equivalent of CD34− stained cells within thoracic aorta | ||||
|
|||||
Media | Side population-progenitor cells | Side population of cells from the tunica media of mouse aorta | Sca1+, cKit(dim), | Differentiate into |
|
CD34−, lineage negative | (These cells were heterogenous) | ||||
Multipotent vascular stem cells ( |
|
SM-MHC(−), Sox1+, Nestin+ |
|
Tang et al., 2012 [ | |
CD146−, CD34−, CD31− | |||||
Differentiate into |
EPCs: endothelial progenitor cells; MSCs: mesenchymal stem cells; NSCs: neuronal stem cells; ECs: endothelial cells; SMCs: smooth muscle cells; PCs: pericytes. Vasculogenic zone: the border between the media and adventitial layer.
Stem cell/hematopoietic markers: CD34, Sca1, and cKit.
MSC markers: CD29, CD44, CD90, and CD105.
EC markers: CD31, vWF, and VEGFR.
The vasa vasorum is a microvascular network that supplies oxygen and nutrients to the walls of large vessel. These conduits consist of a lumen lined by endothelial cells that are surrounded by pericytes or smooth muscle cells. Recent technological advances in image analysis have revealed that the enhanced vascularization in plaques is closely associated with the prognosis of acute arterial occlusion [
In atherosclerotic plaques, the vasa vasorum is considered immature, a characteristic that leads to the microvascular leakage that is responsible for plaque hemorrhage. Because of its high permeability, the vasa vasorum also serves as a conduit for the delivery of inflammatory cells into the plaques. Plaque hemorrhage and inflammatory cell delivery are the key mechanisms underlying the persistence of chronic vascular inflammation and the rapid expansion or rupture of atherosclerotic plaques [
Experimental studies using atherosclerotic models, such as apolipoprotein E- (ApoE-) deficient mice, clearly demonstrate a correlation between vasa vasorum neovascularization and plaque progression [
The findings highlighted above are consistent with an emerging concept suggesting that the expansion of the vasa vasorum causes the progression of atherosclerotic plaques; however, it is still controversial whether the vasa vasorum plays a causative or reactive role in the atherosclerotic process. In some cases, even a low density of vasa vasorum induces neointimal thickening. Khurana et al. reported that the application of the angiogenesis stimulator VEGF to injured rat arterial walls results in, but does not initiate, a marked increase in neointimal thickening [
In atherosclerotic plaques, neovascularization is the primary compensatory response to hypoxia and inflammatory conditions. Neointimal thickening causes ischemia, which strongly induces angiogenesis. Although the expansion of the vasa vasorum in response to neointimal thickening should improve intraplaque ischemia, it does not. Recently, Rademakers et al. investigated the vasa vasorum in plaques of atherosclerotic carotid arteries from aged ApoE-deficient mice by performing
The contribution of vascular-resident stem/progenitor cells to atherosclerosis progression has been confirmed in recent studies utilizing animal models of atherosclerosis with vascular injury. The vascular-resident stem cells are capable of differentiating into myofibroblasts that subsequently migrate to the intima and contribute to the development of neointimal hyperplasia [
In the adventitia, multipotent pericytes and endothelial progenitor cells exist as structural cells of the vasa vasorum. Capillary microvessels also provide a vascular niche to house perivascular stem cells [
Previously, Diaz-Flores et al. reported that in rat femoral arteries that had the adventitial layers removed, the pericytes and endothelial cells of adventitial growing microvessels served as a source of myointimal cells at the intimal thickening and endothelium at the luminal surface, respectively [
Role of the vasa vasorum in atherosclerosis. In atherosclerotic plaque, the vasa vasorum leads to the microvascular leakage that is responsible for hemorrhage and accumulation of inflammatory cells within plaque. Vasa vasorum also serves as the vascular niche for the vascular-resident stem cells (VSCs), including multipotent pericytes and endothelial progenitor cells. Vasa vasorum acts not only as the blood conduit tube but also as a stem cell reservoir to supply VSCs into the intima. VSCs can differentiate into several cells, such as vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and fibroblasts, and can contribute to the atherosclerotic remodeling. Some of VSCs act as pericytes (PCs) to stabilize the vasculature, which attenuate the leakage of blood cells within plaques.
It is well documented that vascular stem cells migrate to the intimal sites and differentiate into myofibroblasts, contributing to neointimal thickening. When Sca1+ cells are transplanted to the adventitial side of vein grafts in ApoE-deficient mice, the cells migrate into the intima and differentiate into smooth muscle cells [
It is well documented that vascular stem cells have potent angiogenic effects through the paracrine effect and/or the differentiation into endothelial cells or pericytes (Table
Antiatherosclerotic therapeutic strategies have been proposed based on findings describing the biology of the vasa vasorum in atherosclerotic plaques [
Moulton et al. reported that blocking vasa vasorum angiogenesis with angiostatin reduces the accumulation of macrophages in plaques and around the vasa vasorum and reduces the progression of atherosclerosis [
It is widely recognized that cholesterol-lowering statin drugs have potent antiatherosclerotic activity [
In addition to the density/expansion of the vasa vasorum, its structural and functional impairment play crucial roles in atherosclerotic plaque development. Fragile neovessels are formed within plaques, reducing perfusion flow regardless of the expansion of intraplaque vasa vasorum that contributes to plaque growth [
The intimate interaction between pericytes and endothelial cells tightly correlates with vascular growth, maturation/stabilization, and remodeling of vessels [
In this review, we discussed the effect of the vasa vasorum on the progression of atherosclerotic plaques with respect to its function not only as a conduit structure that delivers blood components, but also as a stem cell reservoir. A clearer understanding of adventitial vasa vasorum biology would provide insight that would lead to a better understanding of atherosclerotic pathogenesis and improved therapeutic strategies to combat atherosclerotic diseases. Pharmacological inhibition of angiogenesis in atherosclerotic plaques reportedly inhibits lesion progression in animal models. However, it is important to consider that the vasa vasorum acts as either a causative or responsive factor in neointimal formation depending on the atherosclerotic stage. Prior to designing clinical studies aimed at regulating angiogenesis in atherosclerotic diseases, the stage-dependent role of the vasa vasorum in atherosclerotic plaque development should be fully elucidated.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors were supported by a Grant-in-Aid for Scientific Research from JSPS Kakenhi of Japan (22590765, 22590820), Adaptable and Seamless Technology Transfer Program through Target-Driven R&D, JST (AS231Z03692F), and a grant from The Akiyama Life Science Foundation, Suhara Memorial Foundation, and Mitsubishi Pharma Research Foundation.