Arterial permeability dynamics and vascular disease

Abstract

There is a growing consensus that regional susceptibility to atherosclerosis correlates topographically with an increased endothelial permeability to macromolecules such as low-density lipoprotein. Earlier research suggested that increases in arterial macromolecular permeability accompany the adaptation of the endothelial lining to changes in fluid dynamic shear stress, and that permeability might therefore be chronically increased where the endothelium is exposed to a shear stress environment that changes throughout the day. Thus the temporal variability of hemodynamic stresses at the vessel wall, with time constants of many minutes or a few hours, may affect local susceptibility to disease. Changes in the hemodynamic stresses on the endothelial surface (‘local’ stress) result from the normal variations in more ‘global’ hemodynamic variables such as blood flow rate, heart rate, and flow partition at branches, that occur throughout the day in response to changes in peripheral metabolic demand. Thus, at any given time, the permeability at a site is determined by: (1) the steady-state relationship between the local permeability and local shear stress; (2) the dynamics of the permeability change induced by changes in local shear; and (3) the extent to which the shear stress at the site is affected by changes in the global variables. Regional variations in any or all of these three factors can lead to corresponding variations in endothelial permeability, macromolecular uptake and, apparently, atherosclerotic risk. Among the three factors, the first may be relatively unimportant if most transport takes place while the endothelium is responding to hemodynamic changes. The last two factors suggest two ways in which hemodynamic variability can contribute to regional variations in uptake and disease: those sites that become more permeable in response to a given change in local hemodynamic stress, or are subject to larger changes, may be more susceptible to disease than sites that respond less strongly to a change in shear stress or are exposed to more stable hemodynamic environments. Since little is known about the dynamics of such changes in permeability, this is an important area for experimental exploration. To support such investigations, an initial phenomenological model is proposed relating the time course of vascular permeability changes to the associated response of the endothelium to changes in local wall shear.