Three-Dimensional Imaging of Aortic Tissues in Atherosclerosis.

Recent research has advanced the understanding of atherosclerosis as a transmural chronic inflammatory disease involving all three layers of the arterial wall, including the intima plaque, the media, and the adventitia, which forms the outer connective tissue coat of arteries. Our recent studies have suggested that the adventitia is used by the peripheral nervous system as a conduit for reaching all tissue cells. We also found that the peripheral nervous system, that is, the sensory and sympathetic nervous system, undergoes major remodeling processes involving the neogenesis of axon networks adjacent to atherosclerotic plaques.

Animal Models, Pathogenesis, and Potential Treatment of Thoracic Aortic Aneurysm.

Thoracic aortic aneurysm (TAA) has a prevalence of 0.16-0.34% and an incidence of 7.

The Impact of the Nervous System on Arteries and the Heart: The Neuroimmune Cardiovascular Circuit Hypothesis.

Three systemic biological systems, i.e., the nervous, the immune, and the cardiovascular systems, form a mutually responsive and forward-acting tissue network to regulate acute and chronic cardiovascular function in health and disease.

Pairing of single-cell RNA analysis and T cell antigen receptor profiling indicates breakdown of T cell tolerance checkpoints in atherosclerosis.

Atherosclerotic plaques form in the inner layer of arteries triggering heart attacks and strokes. Although T cells have been detected in atherosclerosis, tolerance dysfunction as a disease driver remains unexplored. Here we examine tolerance checkpoints in atherosclerotic plaques, artery tertiary lymphoid organs and lymph nodes in mice burdened by advanced atherosclerosis, via single-cell RNA sequencing paired with T cell antigen receptor sequencing.

Aging impairs the neurovascular interface in the heart.

Aging is a major risk factor for impaired cardiovascular health. Because the aging myocardium is characterized by microcirculatory dysfunction, and because nerves align with vessels, we assessed the impact of aging on the cardiac neurovascular interface. We report that aging reduces nerve density in the ventricle and dysregulates vascular-derived neuroregulatory genes.

Cardiovascular Brain Circuits.

The cardiovascular system is hardwired to the brain via multilayered afferent and efferent polysynaptic axonal connections. Two major anatomically and functionally distinct though closely interacting subcircuits within the cardiovascular system have recently been defined: The artery-brain circuit and the heart-brain circuit. However, how the nervous system impacts cardiovascular disease progression remains poorly understood.

Novel mechanisms and therapeutic targets in atherosclerosis: inflammation and beyond.

This review based on the ESC William Harvey Lecture in Basic Science 2022 highlights recent experimental and translational progress on the therapeutic targeting of the inflammatory components in atherosclerosis, introducing novel strategies to limit side effects and to increase efficacy. Since the validation of the inflammatory paradigm in CANTOS and COLCOT, efforts to control the residual risk conferred by inflammation have centred on the NLRP3 inflammasome-driven IL-1β-IL6 axis. Interference with the co-stimulatory dyad CD40L-CD40 and selective targeting of tumour necrosis factor-receptor associated factors (TRAFs), namely the TRAF6-CD40 interaction in macrophages by small molecule inhibitors, harbour intriguing options to reduce established atherosclerosis and plaque instability without immune side effects.

Neuroimmune cardiovascular interfaces in atherosclerosis.

Two pairs of biological systems acting over long distances have recently been defined as major participants in the regulation of physiological and pathological tissue reactions: i) the nervous and vascular systems form various blood-brain barriers and control axon growth and angiogenesis; and ii) the nervous and immune systems emerge as key players to direct immune responses and maintain blood vessel integrity. The two pairs have been explored by investigators in relatively independent research areas giving rise to the concepts of the rapidly expanding topics of the neurovascular link and neuroimmunology, respectively. Our recent studies on atherosclerosis led us to consider a more inclusive approach by conceptualizing and combining principles of the neurovascular link and neuroimmunology: we propose that the nervous system, the immune system and the cardiovascular system undergo complex crosstalks in tripartite rather than bipartite interactions to form neuroimmune cardiovascular interfaces (NICIs).

Visualization of M2 Macrophages in the Myocardium After Myocardial Infarction (MI) Using Ga-NOTA-Anti-MMR Nb: Targeting Mannose Receptor (MR, CD206) on M2 Macrophages.

Introduction And Objectives: Wound healing after myocardial infarction (MI) is a dynamic and complex multiple phase process, and a coordinated cellular response is required for proper scar formation. The current paradigm suggests that pro-inflammatory monocytes infiltrate the MI zone during the initial pro-inflammatory phase and differentiate into inflammatory macrophages, and then switch their phenotypes to anti-inflammatory during the reparative phase. Visualization of the reparative phase post-MI is of great interest because it may reveal delayed resolution of inflammation, which in turn predicts adverse cardiac remodeling.

Neuroimmune cardiovascular interfaces control atherosclerosis.

Atherosclerotic plaques develop in the inner intimal layer of arteries and can cause heart attacks and strokes. As plaques lack innervation, the effects of neuronal control on atherosclerosis remain unclear. However, the immune system responds to plaques by forming leukocyte infiltrates in the outer connective tissue coat of arteries (the adventitia).

Tissue Clearing Approaches in Atherosclerosis.

Recent advances in cardiovascular research have led to a more comprehensive understanding of molecular mechanisms of atherosclerosis. It has become apparent that the disease involves three layers of the arterial wall: the intima, the media, and a connective tissue coat termed the adventitia. It is also now appreciated that arteries are surrounded by adipose and neuronal tissues.

Combined Single-Cell RNA and Single-Cell α/β T Cell Receptor Sequencing of the Arterial Wall in Atherosclerosis.

Although various pro- and anti-inflammatory T cell subsets have been observed in murine and human atherosclerosis, principal issues of T cell immunity remain unanswered: Is atherosclerosis progression critically affected by aberrant T cell responses? Are tolerance checkpoints compromised during atherosclerosis progression? Answers to these questions will determine if we are at the cusp of developing T cell-dependent therapeutic strategies. Rapid advances in single cell RNA sequencing (scRNA-seq) and single cell α/β T cell receptor (TCR) (scTCR) sequencing allows to address these issues in unprecedented ways. The majority of T cells recognize peptide antigen-MHC complexes presented by antigen-presenting cells which, in turn, trigger activation and proliferation (clonal expansion) of cognate TCR-carrying T cells.

Laser Capture Microdissection-Based mRNA Expression Microarrays and Single-Cell RNA Sequencing in Atherosclerosis Research.

A major goal of methodologies related to large scale gene expression analyses is to initiate comprehensive information on transcript signatures in single cells within the tissue's anatomy. Until now, this could be achieved in a stepwise experimental approach: (1) identify the majority of transcripts in a single cell (single cell transcriptome); (2) provide information on transcripts on multiple cell subtypes in a complex sample (cell heterogeneity); and (3) give information on each cell's spatial location within the tissue (zonation transcriptomics). Such genetic information will allow construction of functionally relevant gene expression maps of single cells of a given anatomically defined tissue compartment and thus pave the way for subsequent analyses, including their epigenetic modifications.

Imaging atherosclerotic plaques by targeting Galectin-3 and activated macrophages using (Zr)-DFO- Galectin3-F(ab') mAb.

The high expression of Galectin-3 (Gal3) in macrophages of atherosclerotic plaques suggests its participation in atherosclerosis pathogenesis, and raises the possibility to use it as a target to image disease severity . Here, we explored the feasibility of tracking atherosclerosis by targeting Gal3 expression in plaques of apolipoprotein E knockout (ApoE-KO) mice PET imaging. Targeting of Gal3 in M0-, M1- and M2 (M2a/M2c)-polarized macrophages was assessed using a Gal3-F(ab') mAb labeled with AlexaFluor®488 and Zr- desferrioxamine-thioureyl-phenyl-isothiocyanate (DFO).

Molecular Imaging of Fibroblast Activity After Myocardial Infarction Using a Ga-Labeled Fibroblast Activation Protein Inhibitor, FAPI-04.

Heart failure remains a major source of late morbidity and mortality after myocardial infarction (MI). The temporospatial presence of activated fibroblasts in the injured myocardium predicts the quality of cardiac remodeling after MI. Therefore, monitoring of activated fibroblasts is of great interest for studying cardiac remodeling after MI.

PD-L1 expression on nonclassical monocytes reveals their origin and immunoregulatory function.

The role of nonclassical monocytes (NCMs) in health and disease is emerging, but their location and function within tissues remain poorly explored. Imaging of NCMs has been limited by the lack of an established single NCM marker. Here, we characterize the immune checkpoint molecule PD-L1 (CD274) as an unequivocal marker for tracking NCMs in circulation and pinpoint their compartmentalized distribution in tissues by two-photon microscopy.

Vascular Smooth Muscle Cells Contribute to Atherosclerosis Immunity.

Vascular smooth muscle cells (VSMCs) constitute the major cells in the media layer of arteries, and are critical to maintain the integrity of the arterial wall. They participate in arterial wall remodeling, and play important roles in atherosclerosis throughout all stages of the disease. Studies demonstrate that VSMCs can adopt numerous phenotypes depending on inputs from endothelial cells (ECs) of the intima, resident cells of the adventitia, circulating immune cells, hormones, and plasma lipoproteins.

Publisher Correction: ApoE attenuates unresolvable inflammation by complex formation with activated C1q.

In the version of this article originally published, a sentence was erroneously included in the author contributions, and information regarding second shared authorship was missing from the author contributions. The following should not have been included in the author contributions: "C.W.

ApoE attenuates unresolvable inflammation by complex formation with activated C1q.

Apolipoprotein-E (ApoE) has been implicated in Alzheimer's disease, atherosclerosis, and other unresolvable inflammatory conditions but a common mechanism of action remains elusive. We found in ApoE-deficient mice that oxidized lipids activated the classical complement cascade (CCC), resulting in leukocyte infiltration of the choroid plexus (ChP). All human ApoE isoforms attenuated CCC activity via high-affinity binding to the activated CCC-initiating C1q protein (K~140-580 pM) in vitro, and C1q-ApoE complexes emerged as markers for ongoing complement activity of diseased ChPs, Aβ plaques, and atherosclerosis in vivo.

Targeting mannose receptor expression on macrophages in atherosclerotic plaques of apolipoprotein E-knockout mice using Ga-NOTA-anti-MMR nanobody: non-invasive imaging of atherosclerotic plaques.

Background: Rupture-prone atherosclerotic plaques are characterized by heavy macrophage infiltration, and the presence of certain macrophage subsets might be a sign for plaque vulnerability. The mannose receptor (MR, CD206) is over-expressed in several types of alternatively activated macrophages. In this study, our objective was to evaluate the feasibility of a Gallium-68 (Ga)-labelled anti-MR nanobody (Ga-anti-MMR Nb) for the visualization of MR-positive (MR) macrophages in atherosclerotic plaques of apolipoprotein E-knockout (ApoE-KO) mice.