Vascular Proliferation and Atherosclerosis: New Perspectives and Therapeutic Strategies

Victor J. Dzau, Ruediger C. Braun-Dullaeus, Daniel G. Sedding

Disclosures

Nat Med. 2002;8(11) 

In This Article

Abstract and Introduction

Abstract

In atherosclerosis, the vascular smooth muscle cell (VSMC) contributes to vessel wall inflammation and lipoprotein retention, as well as to the formation of the fibrous cap that provides stability to the plaque. The VSMC can undergo a proliferative response that underlies the development of in-stent restenosis, bypass graft occlusion and transplant vasculopathy. Although the benefit/risk of therapeutic inhibition of VSMC proliferation in atherosclerosis is unclear, experimental and human evidence strongly suggests the therapeutic potential of antiproliferative therapy for in-stent restenosis, bypass graft failure and other vascular proliferative disorders.

Introduction

Atherosclerosis involves multiple processes including endothelial dysfunction, inflammation, vascular proliferation and matrix alteration. Vascular proliferation contributes to the pathobiology of atherosclerosis and is linked to other cellular processes such as inflammation, apoptosis and matrix alterations. The contribution of vascular proliferation to the pathophysiology of in-stent restenosis, transplant vasculopathy and vein bypass graft failure is particularly important. Thus, an emerging strategy for the treatment of those conditions is to inhibit cellular proliferation by targeting cell cycle regulation. Here we will review the current understanding of the pathophysiological mechanisms and the status of molecular and gene therapeutic approaches in vascular proliferative diseases. The understanding of the pathophysiology of atherosclerosis and related vascular diseases has changed over the last decade, providing new perspectives for preventive and therapeutic strategies.

Recent studies have emphasized the involvement of inflammation in mediating all stages of atherosclerosis.[1,2] However, in addition to inflammation, a key process of atherosclerosis involves the proliferation of vascular smooth muscle cells (VSMCs)[3,4,5] (Fig. 1). One precursor of lesion development in humans may be focal accumulation of VSMCs within the intima.[6] The exact function of VSMCs in atherosclerosis is, however, still a subject of debate.[5,6] In early atherosclerosis, VSMCs may contribute to the development of the atheroma through the production of pro-inflammatory mediators such as monocyte chemoattractant protein 1 and vascular cell adhesion molecule, and through the synthesis of matrix molecules required for the retention of lipoproteins.[6] However, VSMCs may also be important in maintaining the stability of the plaque through the formation of a firm fibrous cap. Indeed, in lipid-laden lesions in which the fibrous cap is thin and weak, there is evidence of VSMC apoptosis, especially at the 'shoulder' region, associated with inflammation.[7] In addition, the local inflammatory milieu can induce expression of collagenase and inhibit expression of proteolytic inhibitors, thus rendering the fibrous cap weak and susceptible to rupture.[2,5] In advanced lesions, fibroblasts and VSMCs with extracellular calcification form a fibrocalcific plaque.

Introduction

Atherosclerosis involves multiple processes including endothelial dysfunction, inflammation, vascular proliferation and matrix alteration. Vascular proliferation contributes to the pathobiology of atherosclerosis and is linked to other cellular processes such as inflammation, apoptosis and matrix alterations. The contribution of vascular proliferation to the pathophysiology of in-stent restenosis, transplant vasculopathy and vein bypass graft failure is particularly important. Thus, an emerging strategy for the treatment of those conditions is to inhibit cellular proliferation by targeting cell cycle regulation. Here we will review the current understanding of the pathophysiological mechanisms and the status of molecular and gene therapeutic approaches in vascular proliferative diseases. The understanding of the pathophysiology of atherosclerosis and related vascular diseases has changed over the last decade, providing new perspectives for preventive and therapeutic strategies.

Recent studies have emphasized the involvement of inflammation in mediating all stages of atherosclerosis.[1,2] However, in addition to inflammation, a key process of atherosclerosis involves the proliferation of vascular smooth muscle cells (VSMCs)[3,4,5] (Fig. 1). One precursor of lesion development in humans may be focal accumulation of VSMCs within the intima.[6] The exact function of VSMCs in atherosclerosis is, however, still a subject of debate.[5,6] In early atherosclerosis, VSMCs may contribute to the development of the atheroma through the production of pro-inflammatory mediators such as monocyte chemoattractant protein 1 and vascular cell adhesion molecule, and through the synthesis of matrix molecules required for the retention of lipoproteins.[6] However, VSMCs may also be important in maintaining the stability of the plaque through the formation of a firm fibrous cap. Indeed, in lipid-laden lesions in which the fibrous cap is thin and weak, there is evidence of VSMC apoptosis, especially at the 'shoulder' region, associated with inflammation.[7] In addition, the local inflammatory milieu can induce expression of collagenase and inhibit expression of proteolytic inhibitors, thus rendering the fibrous cap weak and susceptible to rupture.[2,5] In advanced lesions, fibroblasts and VSMCs with extracellular calcification form a fibrocalcific plaque.

Figure 1.

Function of VSMCs during different stages of atherosclerosis. Cardiovascular risk factors alter the vascular endothelium (EC), which triggers a cascade of events, including the recruitment of leukocytes. Cytokines and growth factors are released by inflammatory cells and vascular cells, generating a highly mitogenic milieu. VSMCs migrate, proliferate and synthesize extracellular matrix components on the luminal side of the vessel wall, forming the fibrous cap of the atherosclerotic lesion. Inflammatory mediators ultimately induce thinning of the fibrous cap by expression of proteases, rendering the plaque weak and susceptible to rupture and thrombus formation. In advanced disease, fibroblasts and VSMCs with extracellular calcification give rise to fibrocalcific lesions. LDL, low-density lipoprotein; MCP, monocyte chemoattractant protein; VCAM, vascular cell adhesion molecule; PDGF-BB, platelet-derived growth factor (BB, -chain homodimer); TNF, tumor necrosis factor; TGF, transforming growth factor; IL, interleukin 1; IGF, insulin-like growth factor; bFGF, basic fibroblast growth factor; Ang II, angiotensin II; EGF, epidermal growth factor; IFN, interferon.

The origin of VSMCs in the atherosclerotic plaque is intriguing. Intimal thickening appears during normal development and aging[8] Intimal VSMCs, including those in atherosclerotic lesions, are reportedly monoclonal in origin.[9] This would indicate that the neointima arises from proliferation of resident pre-existing clonal VSMCs. Although examination of human atherosclerotic lesions has not yielded evidence of extensive replication,[10,11] it may occur very early or at a low rate throughout the development of atherosclerosis or episodically at a high rate. Indeed, VSMCs have been identified in fatty streaks of young individuals.[12] Experimental data also indicate that intimal VSMCs may originate from the media or the adventitia.[13] Furthermore, embryonic endothelial cells are reportedly able to transdifferentiate into mesenchymal cells expressing smooth muscle cell actin.[14] Animal studies have indicated that neointimal cells may also originate from subpopulations of bone marrow- and non-bone marrow-derived circulating cells.[15,16,17,18] In models of hyperlipidemia-induced atherosclerosis, as well as in post-angioplasty restenosis and graft vasculopathy, bone marrow cells may give rise to a substantial percentage of the VSMCs that contribute to arterial remodeling. The contribution of these cells to human atherosclerosis has not been proven, although circulating smooth muscle progenitor cells have been identified in human peripheral blood.[19]

In summary, the function of the intimal smooth muscle cell in the natural history of the atherosclerotic lesion seems to be to act as a nidus for development of the lesions, perhaps by accelerating lipid accumulation or macrophage chemotaxis. Proliferation is probably an early event, followed by a chronic process that provides an essential fibrous cap that prevents plaque rupture.

Several vascular diseases involve VSMC proliferation as the primary pathophysiologic mechanism. These clinical conditions include in-stent restenosis, transplant vasculopathy and vein bypass graft failure.[20] Ironically, these conditions develop as consequences of the procedures used to treat occlusive atherosclerotic diseases. Indeed, 30-40% of patients undergoing percutaneous balloon angioplasty will develop restenosis within the first 6 months.[21] With the recent deployment of stents, this incidence is now about 20%, still an unacceptably high rate.[21] Vein graft failure ranges from 10 to 30% per year.[22] These vascular proliferative diseases are initiated by mechanical, biochemical or immunological injury to the vessel wall. Vascular injury triggers a cascade of events that includes endothelial denudation or dysfunction, inflammation and VSMC activation and proliferation. Myriad growth factors and cytokines can be detected in human vascular lesions. These mediators may be released by dysfunctional endothelial cells, inflammatory cells, platelets and VSMCs, mediating chemoattraction, cell migration, proliferation, apoptosis and matrix modulation.[3]

Understanding of the responses of growth factors and VSMC proliferation to vascular injury is derived mainly from studies involving animal models of arterial injury. Direct data are difficult to obtain from human disease. In the rat model, basic fibroblast growth factor, released from dying vascular cells, can initiate medial proliferation of VSMCs,[23] whereas platelet-derived growth factor may induce subsequent migration of VSMCs toward the intima.[24] Intimal proliferation and matrix accumulation occur under the influence of platelet-derived growth factor, transforming growth factor- , angiotensin II, epidermal growth factor and insulin-like growth factor 1.[25,26,27,28] Furthermore, loss of growth-inhibitory factors, occurring as a result of decreased endothelial cell secretion of nitric oxide (NO), inactivation of NO by reactive oxygen species or altered heparan sulfate proteoglycan synthesis, may also contribute to the migration and proliferation of VSMCs and to the increased inflammatory response.[29,30]

With the recognition of the essential involvement of VSMC proliferation in the conditions described above and the improved understanding of the molecular and cellular mechanisms of cellular proliferation, antiproliferative therapeutic modalities have become a focus of research and development. In the following sections, we review the mechanisms of vascular proliferation and cell cycle regulation and examine the therapeutic potential of targeting these processes.

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