Endothelium exposed to atheroprone flow promotes monocyte transmigration and specification

Abstract

Atherosclerosis and its consequences, myocardial infarction and stroke continue to be the leading cause of mortality worldwide. Despite recent progress in our understanding of the initiation and progression of atherosclerosis, there is an increasing need to identify novel signaling pathways with potential therapeutic targeting. One of the earliest events in atherogenesis is endothelial dysfunction triggered by disturbed flow characteristic of atherosclerosis susceptible regions. This event is followed by monocyte transmigration and differentiation into macrophages. To mechanistically dissect the contribution of atheroprone flow on the endothelial cell phenotype and monocyte transmigration and specification, we have developed a novel in vitro model in which endothelial cells (EC) are seeded on a collagen gel and exposed to athero‐prone and ‐protective shear stress waveforms. Using this model, we have demonstrated that atheroprone but not atheroprotective flow promotes monocyte recruitment via a Krüppel Like Factor‐2‐dependent pathway. Furthermore, we have documented that transmigrated monocytes under atheroprone flow polarize toward a pro‐inflammatory phenotype as measured by gene expression of a set of pro‐inflammatory markers. This work supports the hypothesis that the hemodynamic environment promotes EC‐monocyte interactions, which are a key determinant of macrophage polarization.