Abstract 147: Coordinate Regulation of Chemo-attractive And -repulsive Guidance Cues Instructs Leukocyte-endothelial Interactions in Atherosclerosis
Leukocyte influx into the arterial wall plays a critical role in the development and progression of atherosclerosis. Emerging evidence suggests that neuronal guidance cues, typically expressed during development, are involved in both physiological and pathological immune responses. We hypothesized that endothelial expression of such guidance cues plays a role in regulating leukocyte trafficking into the vascular wall during atherogenesis. Gene expression profiling revealed that members of the Netrin, Semaphorin and Ephrin family of guidance molecules are differentially regulated in athero-prone and athero-protected regions of the aortae of Ldlr-/- mice. Netrin-1 and Semaphorin 3A are highly expressed in the outer curvature of the aorta, and potently inhibit chemokine-directed migration of monocytes in vitro. Endothelial expression of these negative guidance cues is down-regulated by pro-atherogenic factors associated with monocyte entry into the vessel wall, including oscillatory shear stress and pro-inflammatory cytokines. Furthermore, using intravital microscopy we show that in vivo delivery of Netrin-1- or Semaphorin3A-blocking peptides increases leukocyte adhesion to the endothelium ~2-fold compared to the control peptides. Conversely, we show that a guidance cue that is highly expressed in atheroprone regions of the aorta, EphrinB2, is up-regulated in endothelium cells under pro-atherosclerotic flow conditions (eg. oscillatory shear stress, pro-inflammatory cytokines) and functions as a monocyte chemoattractant. These data suggest a new paradigm for leukocyte-endothelial interactions in which the coordinate regulation of chemo-attractive and -repulsive guidance cues regulates leukocyte trafficking in health and disease.
- © 2013 by American Heart Association, Inc.