Vascular smooth muscle cells (VSMCs) may be considered end-effector organs of the vasculature. They mediate the vasomotor responses orchestrated by the endothelium and are the principal pathogenic agents in diseases such as atherosclerosis, restenosis, and hypertension. Indeed, VSMCs represent an ideal target for the therapy of these conditions.

In atherosclerosis, for example, endothelial cells (ECs) and macrophages are primarily involved in the initiation of this disease, whereas VSMCs are typically the last to manifest pathological change (Table 61–1). However, once they do, the proliferative, synthetic, and matrix-modulating capacities of VSMCs underlie obstructive lesion formation and play a critical role in determining plaque stability (1).

VSMCs are highly responsive to their environment and are able to switch their phenotype from quiescent and contractile to migratory, synthetic, and proliferative (2). Various cues from the surrounding milieu, such as hormonal signals from overlying ECs, cytokines from invading macrophages, and mechanical stresses on the vessel wall, can both initiate and sustain the modulation of VSMC form and function.

Under normal conditions, ECs lining the arterial lumen act as sentinels and gatekeepers. By virtue of their location, ECs are the first to respond to circulating factors and hemodynamic stresses, rapidly relaying these signals to VSMCs for transduction (3). ECs also prevent circulating cells and macromolecules, such as lipids or plasma proteins, from penetrating the underlying intima and media indiscriminately. This insulates the underlying VSMCs from stimuli that might otherwise activate them or initiate their phenotypic conversion. However, when ECs become diseased or damaged this barrier function may fail (4). Under these circumstances, ECs elaborate molecular “alarm bells” that initiate inflammatory cell adhesion (5), thrombosis, vasoconstriction, and eventually VSMC proliferation.