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- ↵*Reprint requests and correspondence:
Dr. Richard T. Lee, Partners Research Facility, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA.
Although percutaneous transluminal angioplasty is widely used to treat patients with vascular diseases, restenosis remains a major limitation, affecting about one-third of patients (1–4). Despite the benefits of stent implantation and brachytherapy, as well as the new excitement over drug-eluting stents, restenosis will remain a challenging problem (1–3). These advances of interventional technologies will encourage us to push the threshold of intervention further by approaching more difficult lesions in smaller vessels, and what we now consider to be clinically insignificant restenosis will become important.
Until recently, the translation of basic vascular biology studies into clinically effective therapies for restenosis has largely been a failure (3). Many therapies inhibited intimal proliferation in animals, but few worked in humans. Whenever basic laboratory science seems to stumble like this, there are many possibilities, such as differences between species and deficiencies in our experimental models. Another major reason for a mismatch between the laboratory and the clinic is that central assumptions of the pathophysiology are incorrect, so that researchers are looking for the wrong things in the laboratory, or perhaps even testing the wrong hypotheses. When this occurs, it sometimes takes a revolution in thinking to set things straight.
We are in the midst of such a revolution in all fields of tissue repair, and vascular injury is no exception. The apparent ability of some adult progenitor cells, either circulating or endogenous within a tissue, to change phenotype dramatically is leading us to reconsider theories of tissue repair. Although this revolution is just beginning, and major controversies abound, it is already clear that our textbook figures of intimal cells arising from migration out of the existing media will require revision. In fact, major questions are arising about what defines a given type of cell, and many of our usual histopathologic classifications of cells in the tradition of Virchow may also need revision. Careful use of multiple specific cell markers is already suggesting that some cells are not what we think they are (5).
Restenotic lesions following arterial intervention are different from typical atherosclerotic plaques. Whereas atherosclerotic plaques accumulate lipid, calcification, and fibrosis, restenotic lesions are typically a more homogeneous mix of cells and extracellular matrix. Early studies suggested that injury that denudes the endothelial layer induces platelet and fibrin deposition immediately after injury, subsequently stimulating vascular smooth-muscle cell migration, proliferation, and extracellular matrix synthesis. Thus, early attempts to limit restenosis logically focused on antithrombotic mechanisms or strategies to slow smooth-muscle cell proliferation; most failed to inhibit restenosis in humans (1,3,6).
On the basis of the biology of wound healing, a role of inflammation in the development of restenosis also emerged (1,4). Thrombus formation or the injury itself initiates recruitment of leukocytes to the injury (1,7). The interaction between platelets and leukocytes may amplify the inflammatory response, as the binding of leukocytes to platelets induces leukocyte activation steps such as integrin activation and chemokine synthesis. The increase in the expression of adhesion molecules on neutrophils and monocytes and circulating levels of inflammatory markers correlate with the incidence of restenosis in humans, and inhibition of inflammation by inhibiting chemokine receptors or adhesion molecules attenuates neointima formation in animal models (1,8–10). This supports the important role of inflammatory cells in neointima formation.
In these and other models of restenosis, endogenous smooth muscle cells from the intima, media, and adventitia are the source of proliferating cells and extracellular matrix (1,4,8,11). This traditional scheme has now been challenged by studies showing that circulating blood contains vascular smooth muscle cell progenitors that contribute to the formation of vascular lesions. Several reports showed that in transplant atherosclerosis, donor intimal smooth muscle cells are derived from host bone marrow cells (12–14). Subsequently, it was demonstrated that bone marrow-derived cells contribute to neointima formation in vascular injury (15). Furthermore, bone marrow cells or blood mononuclear cells can differentiate into cells with vascular smooth muscle cell markers (15,16).
Dendritic cells, so named because of their long membrane extensions, are specialized innate immunity cells. These professional antigen-presenting cells constitutively express high levels of both class I and class II MHC molecules and members of the co-stimulatory B7 family. After capturing antigen in tissues by phagocytosis or endocytosis, dendritic cells migrate into the blood or lymph and circulate to various lymphoid organs, where they present antigens to T lymphocytes. Dendritic cells are not a single cell type, but a system of cells that arise from distinct lineages with different functions (17–19). Although the principal function of dendritic cells is to induce T-cell immunity by presenting antigens to T lymphocytes, dendritic cells are also essential to maintain self-tolerance by inducing apoptotic cell death of potentially harmful self-reactive T-cells (17,20).
In this issue of the Journal, Bauriedel et al. (21)identify dendritic cells at the site of vascular injury by immunostaining with OX-62 and S100 antibodies and with electron microscopy. These cells first appear as adherent cells along the internal elastic lamina four days after injury, and at day 7, they constitute approximately half of the cellular content of neointima. Thereafter, numbers of cells with dendritic antigens decrease, whereas OX-62 immunoreactive cells are still evident along the luminal surface of advanced neointima at day 28. The study also demonstrates that these dendritic cells express Bcl-2 and HSP47 during all stages of neointima development. Although this study did not define a functional role for dendritic cells in the development of neointima, these new data raise interesting questions. Relatively little is known about subpopulations of rat dendritic cells compared with mouse or human dendritic cells, but rat dendritic cells can also be classified into subsets that elicit different functions in immunologic reactions (17,19,22,23). In mice and humans, using expression of surface markers such as CD4, CD8, and CD11, dendritic cells can be grouped as myeloid dendritic cells or DC1, and lymphoid dendritic cells or DC2, which exhibit different functions. In general, myeloid dendritic cells can produce large amounts of interleukin 12 upon exposure to pathogens and drive T-cells to differentiate into Th1 cells; lymphoid dendritic cells produce large amounts of interferons upon exposure to virus and drive differentiation of Th2 cells (17,20). Although OX-62 antigen (αϵ-integrin) may be preferentially expressed on lymphoid dendritic cells (19,22), identification of dendritic cell subsets present in neointima would provide important insight in the role of dendritic cells in neointima formation.
In addition, this study demonstrated that not only the proportion of dendritic cells in neointima, but also the absolute number of dendritic cells decreases during the development of neointima (21), which suggests that dendritic cells migrate out from the lesion. If this is the case, these cells might migrate back to lymphoid tissues, where they modulate T-cell functions. It may also be conceivable that these dendritic cells transdifferentiate into vascular smooth muscle-like cells and form cells of the neointima. Recent studies show that mononuclear cells in human blood can give rise to cells positive for vascular smooth muscle cell markers (16), and most dendritic cells are thought to originate from hematopoietic stem cells and to share some initial steps of their differentiation with monocytes (17,24).
Our reassessment of where cells of the injured vessel are coming from, who they are, and what they are doing is just beginning. Examination of the involvement of dendritic cells in vascular lesions in other animal models as well as humans and identification of subsets of dendritic cells present in vascular lesions are important issues. Identification of the origin and the fate of dendritic cells in vascular lesions will provide important insights in the biology of vascular lesions and perhaps clues to new therapeutic options for restenosis.
☆ Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
- American College of Cardiology Foundation
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