The Role of Age-Related Intimal Remodeling and Stiffening in Atherosclerosis.

Age-related vascular stiffening is closely associated with cardiovascular risk. The clinical measure of arterial stiffness, pulse wave velocity, reflects bulk structural changes in the media observed with age, but does not reflect intimal remodeling that also drives atherosclerosis. Endothelial barrier integrity is disrupted during early atherogenesis and is regulated by the mechanics and composition of the underlying intima, which undergoes significant atherogenic remodeling in response to age and hemodynamics. Here, we first review the best characterized of these changes, including physiological intimal thickening throughout the arterial tree, fibronectin and collagen deposition, and collagen cross-linking. We then address the most common in vivo and in vitro models used to gain mechanistic insight into the consequences of intimal remodeling. Finally, we consider the impacts of intimal stiffening upon endothelial cell mechanotransduction with emphasis on the emerging impact of increased complexity in cellular traction forces and substrate rigidity upon endothelial barrier integrity.