Cellular origins of atherosclerosis: towards ontogenetic endgame? TERENCE M. DOHERTY, PREDIMAN K. SHAH, AND TRIPATHI B. RAJAVASHISTH 1 Atherosclerosis Research Center, Division of Cardiology, Department of Medicine and the Burns and Allen Research Institute, Cedars-Sinai Medical Center and David Geffen School of Medicine at UCLA, Los Angeles, California, USA Conventional wisdom has successfully chronicled in exquisite detail the complex interplay of patho- logic processes leading to the formation of athero- sclerotic plaque and neointimal proliferation after arterial injury. Conventional therapy spawned from conventional wisdom has, unhappily, achieved con- siderably less notable success affecting outcomes of both. Atherosclerosis-based diseases exact a tremen- dous human and fiscal toll, and the road ahead looks grim: as antibiotic usage in underdeveloped areas of the world accelerates, cardiovascular disease will soon overtake infection as the leading cause of death and disability in the entire world (1, 2). To be sure, there have been some clear wins, such as in the case of the efficacy of statin therapy in improving cardio- vascular outcomes. But why the mismatch between our understanding of the pathology and our ability to measurably affect its long-term impact? It may now be time to rethink fundamental conceptions regarding the nature of atherosclerosis. THE CONVENTIONAL MODEL OF VASCULAR DISEASE From within the box, atherosclerosis is a chronic fibroproliferative inflammation of the arterial wall brought about and exacerbated by the dynamic interaction of disordered lipid metabolism and other insults and risk factors with homeostatic mechanisms designed to protect against such injury (3–5). De- cades of research have illuminated pathophysiologic details and provided a mechanistic and conceptual framework. Serum lipoproteins diffusing through extracellular space become entangled in the suben- dothelium and begin to undergo oxidative and cova- lent modifications that render them proinflamma- tory. Overlying endothelial cells (ECs) become affected, and the alert goes out. The troops of the immune and mononuclear phagocytic systems con- verge on the scene, guided by adhesive homing signals expressed by ECs. The ensuing maelstrom of cytokines, growth factors, mitogens, and morphogens instigates smooth muscle cells (SMCs) to migrate from the medial layer into the intima, differentiate toward a synthetic phenotype, and proliferate. But many of the cells recruited to resolve the problem become part of the problem when they find themselves unable (or unwilling) to escape, and in cytotoxic microenvironments they undergo apoptosis and re- lease their proinflammatory contents into the nas- cent plaque. Some of the SMCs are caught in the cytokine crossfire and succumb (6), further exacer- bating the inflammatory nidus. Additional signals are sent calling for more help, and a vicious spiral of inflammation can then occur. The homeostatic bal- ance between normal proteolytic remodeling and inhibition of extracellular proteolytic activity may be tipped toward excessive tissue destruction (7). Struc- tural deterioration can result in erosion or rupture of the plaque cap, which directly precipitates arterial thrombosis with frequently disastrous consequences (8 –10). In arterial plaque, there are a number of cell types (among them mononuclear phagocytes, T cells, B cells, natural killer cells, and mast cells), all thought to originate from circulating hematopoietic and immune precursors. But two key cell types—ECs and SMCs—are presumed to be resident arterial cells. Almost three decades ago Benditt and Benditt found that plaques contain a monoclonal population of cells (11). Work from the Schwartz laboratory and elsewhere confirmed and extended these observations to formulate the monoclonal hypothesis. According to this model, pro- liferating arterial cells are derived from specific SMC clones (12) or clonal expansion of rare resident arterial progenitor cells in response to specific stimuli (13). Monoclonal expansion is a frequent feature even of normal arteries (14), and mutations and derangements of chromosomal architecture are often found in mono- clonal cells of a lesion (15, 16). These findings even led to the more extreme model that views plaque as a benign SMC tumor in the arterial wall (17). But all models of atherosclerosis share a heavy reliance upon two pivotal features: increased adhesiveness of ECs, and migration and proliferation of SMCs— both presumed to be resident arterial cells. 1 Correspondence: Atherosclerosis Research Center, Divi- sion of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, Davis Research Bldg., Room 1062, 8700 Beverly Blvd., Los Angeles, CA 90048-1865, USA. E-mail: rajavashisth@cshs.org 592 0892-6638/03/0017-0592 © FASEB