Elevated Neuropeptide Y in Endothelial Dysfunction Promotes Macrophage Infiltration and Smooth Muscle Foam Cell Formation.

Bongkun Choi,Eun-Young Kim,Halim Lee,Jae-Kwan Song,Eun-Ju Chang,Ji-Eun Park,Min-Kyung Shin,Seong Who Kim

doi:10.3389/fimmu.2019.01701

Bongkun Choi, Eun-Young Kim + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2019.01701

Copy DOI

Abstract

Endothelial dysfunction has been linked to vascular inflammation and foam cell formation but the underlying mechanisms still remain unclear. We sought to define the factors inducing inflammation and smooth muscle foam cell formation under endothelial dysfunction using endothelial nitric oxide synthase (eNOS)-deficient mice. Vascular smooth muscle cells (VSMCs) from eNOS-deficient mice displayed increased expression of macrophage-related genes and elevated lipid uptake. Neuropeptide Y (NPY) was upregulated in the aorta from the eNOS-deficient mice and promoted macrophage chemotaxis toward VSMCs while enhancing the activity of matrix metalloproteinase-3. Notably, NPY induced lipid uptake in VSMCs, facilitating smooth muscle foam cell formation, in association with enhanced expression of genes related to modified low-density lipoprotein uptake and macrophages. NPY was augmented by inflammatory pentraxin 3 (PTX3) in VSMCs. PTX3 enhanced macrophage migratory capacity through the NPY/neuropeptide Y receptor axis and this effect was attenuated by pharmacological inhibition with a receptor-specific antagonist. These observations suggest that endothelial dysfunction leads to the elevation of NPY that amplifies vascular inflammation by increasing inflammatory cell chemotaxis and triggers smooth muscle foam cell formation.

Highlights

Endothelial dysfunction leads to increased permeability and subendothelial retention of modified low-density lipoprotein (LDL) particles, which trigger the subsequent recruitment of monocyte/macrophages into the subendothelial intima [1] and the initiation of plaque formation in the intima of blood vessels [2]
ENOS−/− Vascular smooth muscle cells (VSMCs) expressed elevated levels of colony stimulating factor 1 receptor (CSF1R, known as c-fms), macrophage colony stimulation factor (M-CSF) receptor, and SPI1 which cause phenotypic changes of VSMCs to phagocytic cells [34] (Figure 1C), suggesting that endothelial nitric oxide (NO) synthase (eNOS) deficiency may lead to enhanced lipid uptake by VSMCs by altering the expression of key genes implicated in the uptake of LDL
Endothelial dysfunction characterized by reduced NO bioavailability is an early marker for atherosclerosis [3] and previous reports demonstrated that eNOS protects against atherosclerosis, while eNOS deficiency leads to increased atherosclerosis in a mouse model [30, 31]

Summary

Introduction

Endothelial dysfunction leads to increased permeability and subendothelial retention of modified low-density lipoprotein (LDL) particles, which trigger the subsequent recruitment of monocyte/macrophages into the subendothelial intima [1] and the initiation of plaque formation in the intima of blood vessels [2]. Endothelial dysfunction due to reduced nitric oxide (NO) bioavailability is an early marker for atherosclerosis [3]. Atherosclerosis is the result of complex interactions involving endothelial dysfunction with lipoprotein accumulation, inflammatory infiltration, foam cell formation, and smooth muscle cell alterations [2]. Role of NPY in SMC Foam Cell vasoprotective effects, such as vasodilation, suppression of smooth muscle cell proliferation and migration, and inhibition of inflammatory responses [3]. NO prevents oxidative modification of LDL cholesterol [4], and a defect in the production or activity of NO leads to endothelial dysfunction

Objectives

Methods

Results

Conclusion