Endothelial Expression of Guidance Cues in Vessel Wall Homeostasis Dysregulation Under Proatherosclerotic Conditions

Abstract

Objective 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 may regulate leukocyte trafficking into the vascular wall during atherogenesis. Approach/Results We demonstrate that members of the Netrin, Semaphorin and Ephrin family of guidance molecules are differentially regulated under conditions that promote or protect from atherosclerosis. Netrin-1 and Semaphorin3A are expressed by coronary artery endothelial cells and potently inhibit chemokine-directed migration of human monocytes. Endothelial expression of these negative guidance cues is down-regulated by pro-atherogenic factors, including oscillatory shear stress and pro-inflammatory cytokines associated with monocyte entry into the vessel wall. Furthermore, we show using intravital microscopy that inhibition of Netrin-1 or Semaphorin3A using blocking peptides increases leukocyte adhesion to the endothelium. Unlike Netrin-1 and Semaphorin3A, the guidance cue EphrinB2 is up-regulated under pro-atherosclerotic flow conditions and functions as a chemoattractant, increasing leukocyte migration in the absence of additional chemokines. Conclusions The concurrent regulation of negative and positive guidance cues may facilitate leukocyte infiltration of the endothelium through a balance between chemoattraction and chemorepulsion. These data indicate a previously unappreciated role for axonal guidance cues in maintaining the endothelial barrier and regulating leukocyte trafficking during atherogenesis.

The Neurorepellent Slit2 Inhibits Postadhesion Stabilization of Monocytes Tethered to Vascular Endothelial Cells

“…Thus, Slit2 could represent an exciting therapeutic candidate to simultaneously inhibit the individual events that collectively promote the initiation and progression of vascular inflammation associated with atherosclerosis. Other guidance cues, such as ephrin B2, netrin1, and semaphorin 3E, are differentially regulated in proatherogenic conditions; however, overall, these factors appear to exacerbate, and not attenuate, progressive vascular injury (47)(48)(49). Further studies are needed to determine whether Slit2 is unique among these cues, preventing early trafficking of monocytes into affected vessels, as we report in this article, as well as advanced lesion progression.…”

RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension

“…The latter have important functional consequences on angiogenesis and on the PA response to injury that relate directly to the development of PAH. We focused on COL4 and EFNA1 in particular, because both genes were downregulated in the RNAseq analysis, and both have important, intertwining roles in endothelial biology; COL4 is a major component of vascular basement membranes and EFNA1 is an EC guidance molecule (29) that induces the release of COL4 from these cells (21). Loss of BMPR2 signaling also impaired the ability of PAECs to produce COL4 and EFNA1 by a mechanism that was reproduced by reducing b-catenin, a previously reported downstream effector of BMPR2 gene regulation (4).…”

Macrophages and Dendritic Cells

“…113 The production and secretion of repulsive neuroimmune guidance cues such as netrin-1, ephrin-B, and semaphorins 3A and 3E may contribute to macrophage retention. [114][115][116][117] Hypercholesterolemia also impairs the migration of dermal DCs to regional lymph nodes through generation of platelet-activating factor. 118 Oxidized, but not native LDL, inhibits TLR4-induced peritoneal macrophage efflux into lymphatics and in vitro migration through a process that involves CD36, inactivation of Src homology 2-containing phosphotyrosine phosphatase, sustained activation of focal adhesion kinase, and alteration of cytoskeletal dynamics.…”