The artery wall consists of three principal layers (Figure 1): the intima, media and adventitia. The endothelial cells are in direct contact with blood and they are acted upon by the normal and shearing forces of blood flow (pressure and wall shear stress) as well as the circumferential stress induced by cyclic strain driven by the pressure pulse. All of these forces (P, WSS, and CS) can induce biomolecular changes in EC, although the literature is dominated by studies of the effects of WSS. The medial layer provides the artery wall with the mechanical strength that is required to support the blood pressure-induced circumferential stress. The higher pressures in the large arteries are supported by thicker-walled vessels with multiple layers of smooth muscle cells (SMC) that play a key role in the development of atherosclerosis and vascular disease. EC, SMC and fibroblasts (FB) are also exposed to forces associated with the interstitial flow driven across the vessel wall by the difference in pressure between the blood vessel lumen (P) and the external tissue pressure (close to 0 mm Hg). These interstitial flow forces also induce biomolecular responses in vascular cells as well as cancer cells.
Atherosclerosis is a disease of the artery wall, and thrombotic events caused by atherosclerosis are by far the most common cause of death in the world. Atherosclerosis is a complex disease (Figure 2) that involves the initial accumulation of blood-borne lipids (e.g., LDL) in the intima followed by an immune response involving leukocyte (monocyte) binding from the blood stream to the endothelium and transmigration to the intima where they are transformed into macrophages that scavenge lipid and enlarge into foam cells. Growth factors (mitogens) released by these intimal macrophages attract smooth muscle cells from the media into the intimal region where they also become enlarged with lipid to form foam cells that create a lesion in the vessel wall. Early signs of these lesions may be present in the aortas of teenagers in the form of “fatty streaks.” Mature lesions develop with age and may form an occlusive plaque blocking blood flow to downstream tissue or a non-occlusive plaque that is vulnerable to rupture and subsequent occlusive thrombus formation. Atherosclerosis does not arise uniformly on arterial surfaces throughout the vasculature, but tends to be localized to specific sites such as branches and curvatures where fluid mechanical factors deviate from their normal patterns in straight vessels.
The role of fluid mechanics in atherosclerosis had its modern origins with work in the early 1960s suggesting that flow separation at sites of curvature, branching or expansion of cross section might be linked to the development of atherosclerosis. Studies in human cadavers showed that early lesions around the artery branches of the abdominal aorta occurred upstream of the flow dividers where WSS was expected to be relatively low. The low WSS hypothesis of atherosclerosis was subsequently supported by numerous studies. Related studies in the carotid artery bifurcation also noted that the WSS reversed its direction from downstream to upstream over a large segment of the pulsatile flow cycle. This fluid mechanical phenomenon was characterized by a new parameter termed the “oscillatory shear index – OSI” that varies between 0 (no reversal over the cycle) to 0.5 (equal segments of forward and reverse WSS). There was a strong correlation between intimal thickening and OSI as well as mean WSS. The flow field in the carotid bifurcation (Fig. 3) has been studied by many to carefully characterize the hemodynamic WSS environment. The notion that low mean WSS and high OSI (WSS reversal) are the dominant fluid mechanical localizing factors in atherogenesis dominates current thinking in the field, although other mechanisms have been proposed.