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Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1868-1871

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1868-1871.)
© 1997 American Heart Association, Inc.

Articles

Cellular Heterogeneity of the Vascular Tunica Media

Implications for Vessel Wall Repair

Charles L. Seidel

From the Department of Medicine, Baylor College of Medicine, Houston, Tex.

Correspondence to Charles L. Seidel, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail cseidel{at}bcm.tmc.edu


Key Words: • neointimal cells • stem cells • vascular wall repair


*    The Problem
up arrowTop
 *The Problem
down arrowDifferentiated Vascular Smooth...
 down arrowSmooth Muscle "Stem" Cells...
 down arrowCells From Distinct Cell...
 down arrowSummary and Conclusions
 down arrowReferences
 
Following arterial injury in adult humans and other mammals, there occurs a thickening of the intimal layer of the vessel wall due to migration of cells from the tunica media and proliferation of these migrated cells, along with any resident intimal cells. This intimal thickening, or neointimal formation, can lead to vessel stenosis or even occlusion and is the cellular basis of all intimal vascular disease. An understanding of this process leading to prevention, retardation, or reversal of intimal thickening would dramatically reduce morbidity and mortality from vascular disease.

The identity of the cells involved in intimal thickening has not been conclusively determined. The morphology, growth properties, and protein expression of cells in the thickened intima are distinct from those of vascular smooth muscle cells within the tunica media or of endothelial cells lining the vessel lumen. There are at least three hypotheses to explain the identity of neointimal cells: (1) They arise from fully differentiated vascular smooth muscle cells within the tunica media. During their migration to and proliferation in the intimal layer, they undergo function-specific modifications, thus acquiring the characteristics ascribed to neointimal cells. (2) They arise from a normally resident population of smooth muscle "stem cells." Such cells may be embryonic or fetal smooth muscle cells that have not fully differentiated or a multipotential cell that could form either neointimal or smooth muscle cells. Unlike differentiated smooth muscle cells, these cells would retain the ability to migrate and proliferate. During migration to and subsequent proliferation within the thickening intima, such cells may acquire additional characteristics of neointimal cells. (3) They arise from a cell lineage within the tunica media that is distinct from that of the smooth muscle cell. The characteristics of these cells may be modulated to those of neointimal cells during the process of intimal thickening. Because these hypotheses are not mutually exclusive, a combination of the three is also possible. The intent of this brief review is to examine the data in support of each of these hypotheses.


*    Differentiated Vascular Smooth Muscle Cells as the Source of Neointimal Cells
up arrowTop
 up arrowThe Problem
 *Differentiated Vascular Smooth...
down arrowSmooth Muscle "Stem" Cells...
 down arrowCells From Distinct Cell...
 down arrowSummary and Conclusions
 down arrowReferences
 
Morphological data at both the light and electron microscopic levels suggest that the tunica media of mammalian elastic and muscular arteries is composed of a homogeneous cell population, the vascular smooth muscle cell.1 2 However, this cellular homogeneity may not be true for all mammals.3 4 Moreover, in avian vessels, two morphologically distinct cell populations have been described,5 6 one with characteristics of muscle cells (large number of myofilaments, attachment bodies, peripheral vesicles, and a basement membrane) and a second population lacking these characteristics. When tunica media cells from mammalian arteries are isolated and cultured, they express many proteins characteristic of cells found in the neointima. Given the morphological homogeneity of medial cells, it follows that neointimal cells with distinctive characteristics must have been derived from the homogeneous population of medial smooth muscle cells through alterations in protein expression. This phenotypic modulation has been described as a shift from a "contractile" phenotype to a "synthetic" phenotype.7 However, the rate at which cells appear in the intima following injury and immunohistochemical data (see the following section) suggest that possibilities need to be considered other than that fully differentiated vascular smooth muscle cells are the sole source of neointimal cells.

In the rat carotid injury model, cell migration from the tunica media is responsible for the vast majority of cells in the neointima.8 In this model as well as in the cuffed rabbit carotid model,9 cells are already present within the intima 3 days after injury. Because these species have few if any resident intimal cells, cell migration from the medial layer must be occurring rapidly. This implies a rapid shift from a contractile to a migratory phenotype. The processes of cell migration and contraction are both similar and different. They have in common a calcium-dependent regulation of myosin light-chain phosphorylation,10 11 but migration differs, in that it requires the polymerization/depolymerization of actin- and myosin-containing filaments and the making and breaking of cell-matrix contacts. Both of these migratory processes are highly regulated through specific proteins, enzyme cascades, and regional changes in ion concentrations.12 A differentiated vascular smooth muscle cell either would have to contain dual chemomechanical transduction processes, one for contraction and the other for migration, or be able to rapidly (within 3 days) express and degrade the appropriate proteins to shift mechanical functions. Alternatively, a subpopulation of migration-competent cells may exist. Such a population may be represented by the small cohort of cells that has been shown to rapidly (within 33 hours) replicate following injury.8 13 It is not known which of these possibilities is correct.

Work from our laboratory indicates that not all cells within the tunica media are able to migrate.14 We have characterized in vivo and in vitro two distinct cell populations in canine carotid arteries.15 One population has the phenotype of a differentiated vascular smooth muscle cell ("VSMC" in the FigureDown) and represents the majority of cells in the tunica media. The other population ("type 2 cell" in the FigureDown) does not normally express muscle-specific proteins and is embedded within the elastic lamina of the media (see "immunohistochemistry of whole wall" in the FigureDown). Only type 2 cells are found in the neointima following injury, where they express {alpha}-smooth muscle actin. They also expresses {alpha}-actin in vitro and are able to migrate in response to a chemotactic gradient. Cells with a similar phenotype have also been shown to migrate to the neointima in vivo in a porcine injury model.16 In addition, the vascular smooth muscle cell population does not appear to change expression of contractile proteins in culture or acquire the ability to migrate. These data imply that modulation from a differentiated phenotype is not a prerequisite for migration because of the existence of migration-competent cells within the normal tunica media. The migration of this subpopulation of cells could account for the presence of cells in the intima within 3 days of injury. These data also suggest that modulation of contractile protein expression is not a property of all differentiated vascular smooth muscle cells and either does not occur or is the property of a particular cell subset. Immunohistochemical data support the presence of distinct cell populations within the tunica media, obviating the need for modulation of differentiated cells.



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  		Figure 1. Cellular heterogeneity of canine carotid artery as indicated by immunohistochemistry and characteristics of isolated cell populations. Immunohistochemistry of the whole wall (top) illustrates cells that are smooth muscle myosin heavy-chain–positive (red with white nuclei) and muscle myosin–negative (absence of red with blue nuclei) within the tunica media. Smooth muscle myosin–positive cells were isolated (isolated VSMC) and characterized in terms of protein expression, proliferative potential, and migratory ability as well as their presence in the neointima. Smooth muscle myosin–negative cells were isolated (isolated type 2 cells) and characterized in a similar manner (see References 14 and 15 for details). VSMCs had characteristics of differentiated smooth muscle cells whereas type 2 cells had characteristics of myofibroblasts. VSMCs compose the majority of cells within the tunica media whereas type 2 cells are found imbedded within the elastic lamina of the tunica media and in the adventitial layer. Blue nuclei along the luminal surface represent endothelial cells. All images were acquired at a magnification of x20.


*    Smooth Muscle "Stem" Cells as the Source of Neointimal Cells
up arrowTop
 up arrowThe Problem
 up arrowDifferentiated Vascular Smooth...
 *Smooth Muscle "Stem" Cells...
down arrowCells From Distinct Cell...
 down arrowSummary and Conclusions
 down arrowReferences
 
Despite morphological evidence of tunica media cell homogeneity, immunohistochemical data indicate heterogeneity. A variety of proteins have been used as markers for vascular smooth muscle cells (reviewed in Reference 1717 ), but the smooth muscle myosin heavy-chain isoforms SM1 and SM218 appear to be most specific for the smooth muscle lineage. With the use of an SM1/SM2–specific antibody,3 15 19 two populations of cells in the tunica media from adult animals have been identified. One expresses smooth muscle myosin and one does not (see the FigureUp). These latter cells express a nonmuscle myosin heavy chain (nmMHC)15 19 with a molecular weight of 196 kDa.20 In addition, some smooth muscle myosin–positive cells within the media also express nmMHC15 21 or an "embryonic" nonmuscle myosin heavy chain (SMemb)22 23 with a molecular weight of 198 kDa.20 Cells expressing nonmuscle myosins may represent the developmental precursor of differentiated muscle cells.

During vascular development, myosin heavy-chain expression shifts from high expression of nonmuscle forms (nmMHC and SMemb) to high expression of muscle-specific forms (SM1 and SM2).21 22 23 24 25 Frid et al3 have shown that a morphologically distinct cell population in fetal bovine pulmonary artery expresses muscle-specific myosin but that this same cell population in the adult artery does not. Therefore, the presence of cells in the adult animal that express only nonmuscle myosin or that express both muscle and nonmuscle forms suggests that such cells may be immature (embryonic or fetal) smooth muscle cells21 26 from which differentiated smooth muscle cells could arise. If such cells could be isolated in culture and induced to become fully differentiated vascular smooth muscle cells, their role as "stem" cells would be established.

When rat aortic tunica media cells are placed in culture, the proportion of cells that express smooth muscle myosin decreases from 90% in freshly isolated cells, to 45% after 1 week in culture, and to <10% by the fifth passage.27 28 If smooth muscle myosin–positive cells are observed in culture, they express the SM1 but not the SM2 myosin isoform.21 As muscle-specific myosin decreases, the number of cells expressing nonmuscle myosins (nmMHC and SMemb) increases.21 The types of myosins expressed by cultured cells are similar to those expressed by the putative "stem" cells present in vivo, and this culture-induced change in myosin expression has been interpreted as supporting the idea that they are derived by dedifferentiation of vascular smooth muscle cells. However, such isolated "dedifferentiated" smooth muscle cells have never been demonstrated to completely redifferentiate,15 29 30 ie, reexpress both muscle-specific myosins and lose nonmuscle myosins. This suggests either that the proper conditions for differentiation have not been identified or that these cells are truly incapable of differentiating. In addition, the observed changes in myosin expression in culture could result from the differential growth of unique cell populations expressing specific myosins rather than dedifferentiation of a single cell type.

A heterogeneous proliferative response in vivo indicates that not all cells are potential stem cells. Bochaton-Piallat et al31 demonstrated that not all cells within the vessel wall have the same proliferative potential. During development of the rat aorta, they observed that many tunica media cells underwent few (<4) cell divisions before becoming quiescent while others proliferated extensively. In the adult animal, this minimally replicative group represented 70% of the cells. Following aortic injury, few of these cells reentered the cell cycle while those that were highly proliferative during development were stimulated to proliferate and were found in the neointima. We have also observed that the majority of cells isolated from the canine carotid artery appear to be postmitotic (see Reference 1515 and VSMC in the FigureUp). These data clearly indicate that not all cells in the tunica media can serve as stem cells.

Even though the information on "stem" cells is compelling because of the presence of cells in adult vessels that express myosins characteristic of immature cells, their inability to differentiate in vitro suggests that they may not be true stem cells. Such cells may more accurately represent a separate cell population specialized for replication and repair of arterial injury.29 However, it is also possible that a stem cell exists within the vascular wall but has not yet been identified.


*    Cells From Distinct Cell Lineages Serve as the Source of Neointimal Cells
up arrowTop
 up arrowThe Problem
 up arrowDifferentiated Vascular Smooth...
 up arrowSmooth Muscle "Stem" Cells...
 *Cells From Distinct Cell...
down arrowSummary and Conclusions
 down arrowReferences
 
There is increasing evidence that cells from distinct cell lineages comprise the tunica media. A distinguishing feature of cells from a common lineage is that they retain their distinct characteristics when placed under identical growth conditions. Mixtures of cells with distinct characteristics, which include morphology, growth properties, and protein expression, have been isolated from adult mammalian vessels from small and large animals and humans. When such cells are maintained under identical conditions in culture, neither interconversion nor convergence of characteristics has been reported.15 29 30 32 33 34

Both the normal media and the neointima appear to be composed of different admixtures of unique cell populations. Using the limiting-dilution technique, Bochaton-Piallat et al30 isolated four clonal cell lines from the normal rat aortic media and the neointima that had formed 15 days after injury. Regardless of tissue source, the clones had identical characteristics. The only difference was in the relative proportion of each clone in the tissue from which it was isolated (ie, neointima versus normal media). The authors suggested that the neointima comprises the same mixture of cell types as the media, only in different proportions.

The responses of cells in vivo are also consistent with the presence of independent cell lineages. As discussed in the previous section, Bochaton-Piallat et al31 observed that the proliferative potential of cells varied in the rat aorta. This had been previously demonstrated with isolated cells,15 28 30 32 33 34 but the experiments Bochaton-Piallat et al confirmed that this was a property of cells in vivo. Wohrley et al35 also observed that only a specific subpopulation of cells in the fetal bovine pulmonary artery proliferated in response to hypoxia. Finally, it has been shown that a specific cell type migrates to the intima following porcine coronary injury while other cells do not.16 36

These data strongly suggest that there are unique cell populations within the tunica media that retain their characteristics in culture and can be induced to manifest these characteristics (eg, proliferation or migration) under specific circumstances in vivo. The basis of this cell diversity may result from how the tunica media is formed in the embryo. Topouzis and Majesky37 have isolated two smooth muscle cell populations from avian elastic arteries with unique characteristics and have shown that one originates within the cardiac neural crest whereas the other arises from lateral mesoderm-derived mesenchyme. These observations suggest that the embryonic origin of the cells of the tunica media may play an important role in defining the characteristics of the cells.


*    Summary and Conclusions
up arrowTop
 up arrowThe Problem
 up arrowDifferentiated Vascular Smooth...
 up arrowSmooth Muscle "Stem" Cells...
 up arrowCells From Distinct Cell...
 *Summary and Conclusions
down arrowReferences
 
Morphological data suggesting cellular homogeneity of the tunica media has been supplanted by immunohistochemical and cloning data that indicate heterogeneity. This cellular heterogeneity is not restricted to specific species. Although subpopulations of cells with characteristics of immature cells may appear to be stem cells, the inability to demonstrate that they can be modulated into differentiated vascular smooth muscle cells argues against this role and for distinct cell populations. The fidelity of characteristics between cells in vivo and those in vitro, combined with the stability of these characteristics when the cells are placed under common growth conditions, also argues for distinct cell populations. The embryonic origin of these cell lines, the number of lines within a given vessel in a given species, and the forces directing the developmental assembly of these lines into a functioning, mature blood vessel wall remain to be determined. Finally, the contribution of a given cell line to the process of vascular wall repair is unknown.


*    Acknowledgments
 
This work was supported in part by grants from the National Heart, Lung, and Blood Institute (HL-24585 and HL-42550) as well as through the NASA/Texas Medical Center Cooperative Agreement. The author wishes to thank Thorunn Helgason for her excellent technical assistance in the isolation and characterization of the two cell populations from canine carotid tunica media. In addition, the author is grateful for the challenging and critical intellectual discussions with Drs Julius Allen, Mark Entman, and Mark Majesky that helped focus and clarify this review. Finally, the author appreciates the expert secretarial assistance provided by Corneille Smith.


*    Footnotes
 
Arterioscler Thromb Vasc Biol. 1977;17:1868-1871.

Received April 29, 1997; accepted May 6, 1997.


*    References
up arrowTop
 up arrowThe Problem
 up arrowDifferentiated Vascular Smooth...
 up arrowSmooth Muscle "Stem" Cells...
 up arrowCells From Distinct Cell...
 up arrowSummary and Conclusions
 *References
 

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