Ablation of lysozyme M-positive cells prevents aircraft noise-induced vascular damage without improving cerebral side effects

Abstract

Aircraft noise induces vascular and cerebral inflammation and oxidative stress causing hypertension and cardiovascular/cerebral dysfunction. With the present studies, we sought to determine the role of myeloid cells in the vascular vs. cerebral consequences of exposure to aircraft noise. Toxin-mediated ablation of lysozyme M+ (LysM+) myeloid cells was performed in LysMCreiDTR mice carrying a cre-inducible diphtheria toxin receptor. In the last 4d of toxin treatment, the animals were exposed to noise at maximum and mean sound pressure levels of 85 and 72 dB(A), respectively. Flow cytometry analysis revealed accumulation of CD45+, CD11b+, F4/80+, and Ly6G−Ly6C+ cells in the aortas of noise-exposed mice, which was prevented by LysM+ cell ablation in the periphery, whereas brain infiltrates were even exacerbated upon ablation. Aircraft noise-induced increases in blood pressure and endothelial dysfunction of the aorta and retinal/mesenteric arterioles were almost completely normalized by ablation. Correspondingly, reactive oxygen species in the aorta, heart, and retinal/mesenteric vessels were attenuated in ablated noise-exposed mice, while microglial activation and abundance in the brain was greatly increased. Expression of phagocytic NADPH oxidase (NOX-2) and vascular cell adhesion molecule-1 (VCAM-1) mRNA in the aorta was reduced, while NFκB signaling appeared to be activated in the brain upon ablation. In sum, we show dissociation of cerebral and peripheral inflammatory reactions in response to aircraft noise after LysM+ cell ablation, wherein peripheral myeloid inflammatory cells represent a dominant part of the pathomechanism for noise stress-induced cardiovascular effects and their central nervous counterparts, microglia, as key mediators in stress responses.

Redox Switches in Noise-Induced Cardiovascular and Neuronal Dysregulation

“…Using our standardized noise exposure protocol, we reliably report elevation of blood pressure in noise-exposed animals, which exacerbates pre-existing hypertension. Our model also finds increases in leukocyte infiltration into the aortic endothelium, causing endothelial dysfunction ( Kroller-Schon et al, 2018 ) that appears to be phagocytic NADPH oxidase (Nox2) ( Kroller-Schon et al, 2018 ) and macrophage/monocyte-dependent ( Frenis et al, 2021 ). These effects can be prevented by induction of the antioxidant principle nuclear factor E2 related factor-2 (Nrf2)/heme oxygenase 1 (HO-1) axis ( Bayo Jimenez et al, 2021 ), implying a critical link between oxidative stress and the onset of adverse cardiovascular effects of noise.…”

“…These effects can be prevented by induction of the antioxidant principle nuclear factor E2 related factor-2 (Nrf2)/heme oxygenase 1 (HO-1) axis ( Bayo Jimenez et al, 2021 ), implying a critical link between oxidative stress and the onset of adverse cardiovascular effects of noise. This postulate is also supported by numerous oxidative stress markers found in noise-exposed animals such as 3-nitrotyrosine-, malondialdehyde- or 4-hydroxynonenal-positive proteins in different tissues and plasma/serum as well as S-glutathionylated endothelial nitric oxide synthase (eNOS) and uncoupled neuronal nitric oxide synthase (nNOS) and directly measured reactive oxygen species (ROS) formation by high performance liquid chromatography (HPLC)-based quantification of 2-hydroxyethidium and various other staining techniques or oxidative burst ( Munzel et al, 2017 ; Kroller-Schon et al, 2018 ; Kvandova et al, 2020 ; Steven et al, 2020 ; Frenis et al, 2021 ). Classical biomarkers of oxidative stress such as malondialdehyde-, 4-hydroxynonenal or 3-nitrotyrosine-positive proteins (described for various cardiovascular disease conditions Daiber and Chlopicki, 2020 ; Daiber et al, 2021 ) were also observed upon noise exposure.…”

Angiotensin II Induces Oxidative Stress and Endothelial Dysfunction in Mouse Ophthalmic Arteries via Involvement of AT1 Receptors and NOX2

“…Compound (Sakura Finetek Europe, Alphen aanden Rijn, Netherlands), and frozen in liquid nitrogen. Freshly prepared cryosections (10 µm thickness) were incubated with 1 µM of dihydroethidium (DHE, Thermo Fischer Scientific, Waltham, MA, USA) for 30 min at 37 • C. By using an Eclipse TS 100 microscope (Nikon, Yurakucho, Tokyo, Japan) equipped with a DS-Fi1-U2 digital microscope camera (Nikon) and the imaging software NIS Elements (Nikon, Version 1.10 64 bit) the fluorescence (518 nm/605 nm excitation/emission) was recorded and measured in the vascular wall by using ImageJ (NIH, http://rsb.info.nih.gov/ij/) accessed on 11 March 2019 [43,44].…”

In vivo analysis of noise dependent activation of white blood cells and microvascular dysfunction in mice

“…The here described preparation method for measurement of mouse cerebral arteriole reactivity by video microscopy was established by the senior author (A.G.) [11] . Video microscopic measurement methods for arterioles of other vascular beds have previously been described by our working group [5 , 21] . Arterioles branching from the middle cerebral artery (MCA) were selected for measurement, since the MCA and its branches supply the largest part of the cerebral cortex and other brain regions with blood [22 , 23] .…”

“…The influence of noise exposure on microvascular dysfunction, inflammation and changes in blood flow remains the subject of intense investigation at the epidemiological level in large cohorts [1] and at the mechanistic level in mouse studies [2] , [3] , [4] , [5] . Since inflammation ultimately leads to pathophysiological alterations of blood flow and the adherence and diapedesis of leukocytes, visualization of these changes has been the main purpose of various invasive and non-invasive techniques, exposing the vascular network to scientific investigation [6 , 7] .…”