Enhanced interstitial flow as a contributing factor in neointima formation: (shear) stressing vascular wall cell types other than the endothelium

AS BLOOD FLOWS THROUGH the vascular network, it creates fluid mechanical forces that can be predicted based on established physical principles of fluid dynamics. The major components of flow-generated force in the vasculature include pressure and shear stress, both of which are imparted directly onto the vessel wall. The realization that different patterns (laminar vs. oscillatory), magnitudes (high vs. low), and spatial gradients of shear stress can influence the overall vessel homeostasis has led to an intense investigation into how shear stress regulates the structural and functional phenotype of the blood vessel. Through the work of many dedicated laboratories, we are now certain that shear stress exerts a profound effect on endothelial cells which line all vessels. The endothelium, in turn, can communicate the condition of the hemodynamic environment to which it is exposed to underlying vascular components such as smooth muscle and adventitial fibroblasts, resulting in a propagation of shear stress effects to the entire vessel wall. To illustrate this point, changes in shear stress are perceived by the endothelium and converted in biochemical signals, which are then relayed to enzyme systems that generate vasoactive substances such as nitric oxide (NO). Through a paracrine effect, NO activates the molecular machinery that governs smooth muscle contractility, thereby translating changes in shear stress into an alteration of vessel diameter. In the normal, intact vasculature, the endothelial layer forms an interface between the blood and the remaining components of the vascular wall. Thus vascular smooth muscle and adventitial fibroblasts are remote from the actual hemodynamic shear forces. As a result, the direct influence of shear stress on these mural cell types has received little attention. Rather, the stretch generated via the rhythmic expansion and contraction of the vessel wall with each successive pulse of pressure and bloodflow appears to be the dominant hemodynamic stimuli for smooth muscle and, potentially, adventitial cells. Indeed, cyclic stretch has been shown to activate mechanotransduction pathways that lead to functional responses in these cell, and readers are directed to an excellent review in this area (4). So, if smooth muscle and adventitial cells are shielded, in a relative sense, from shear stress and are most responsive to hemodynamic-imposed stretch, the influences of shear stress would seem to be of little concern in these cell types. However, if one considers the forces produced by the flow of interstitial fluid through the vessel wall, then shear stress forces may in fact be an important factor in regulating smooth muscle cells and vessel wall integrity. This concept may have clinical ramifications given that factors which enhance interstitial flow (i.e., chemical or mechanical injury to the endothelium and inflammation and hypertension induced enhancement of vascular permeability) are associated with vessel remodeling and neointima formation. The basic notion that vascular smooth muscle and fibroblasts are responsive to shear stress has been tested by several investigative teams in the past. Laminar shear stress ranging from 10 to