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Muscle cells. --- Myocytes --- Cells

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It is by now widely recognized that atherosclerosis – with its burden of consequences in cerebro- and cardiovascular diseases – is just a chronic inflammatory process of the arterial wall. A very peculiar, complex and as yet still poorly understood process, upon which hundreds of scientists from several different fields are continuously concentrating their investigative efforts in search of possible leads to therapeutic approaches. Initiation of the disease is given by deposition of lipid in the intimal layers, resulting in endothelial activation and infiltration of blood-derived mononuclear cells. These mature into macrophages, become activated, express scavenger receptors such as SR-A and CD36 and ingest the oxidized lipoprotein accumulating in the lesion. Macrophages thus represent an obvious target for intervention, as they play a crucial role in the progression of the atherosclerotic inflammation. Studies have shown that hypercholesterolaemia can increase monocyte mobilisation from bone marrow into the circulation, and several chemokines and their receptors are involved in the recruitment of blood borne monocytes into the arterial wall. Monocyte-derived macrophages are capable of sustaining their local proliferation, but resident macrophages possibly also participate in progression of the disease. Remarkably, smooth muscle cells can acquire macrophage-like features during atherogenesis, including the ability to uptake lipid, thus becoming a significant proportion of the CD68+ so called ‘foam cells’. Lipid-laden macrophages induce extracellular matrix degradation, while lipid uptake eventually causes their death with formation of a necrotic core. The efficiency in clearance of dead cells by phagocytes (efferocytosis), can also be considered as a determinant of plaque vulnerability. An important feature of macrophages is their great plasticity and functional diversity in response to signals from the plaque microenvironment. Several such ‘signals’ (cholesterol, oxidative stress, hypoxia, cytokines…) can in fact modulate cell differentiation at transcriptional and epigenetic levels, thus altering the balance between the effector vs. reparative functions of macrophages. A whole gamut of specific subsets are thus originated, which appear to be simultaneously present in lesions with proportions that vary according to their location, the disease stage, and the presence of additional cell types such as e.g. dendritic cells. The result is a multiplicity of potential pharmacological targets, representing a major obstacle for the devisement of therapeutic strategies. Experimental approaches have been attempted in diverse directions: e.g. modulating the macrophage phenotype to an anti-inflammatory and resolving state, or blocking pro-inflammatory cytokines that macrophages produce, or alternatively enhancing efferocytosis in order to favour the resolution of inflammation and stabilization of plaques. Blocking monocyte recruitment was proposed in order to hinder the initial steps of atherogenesis. Other treatments were aimed to inhibiting local proliferation of pro-inflammatory macrophages. Specific targeting of macrophages has however to date not yet provided significant, translational results. The present Research Topic collects articles to help unravel the complexity of macrophage behaviour in atherosclerosis and identify innovative pharmacological approaches.

Science: general issues --- Pharmacology --- monocytes/macrophages --- inflammation --- foam cell formation --- smooth muscle cells --- atherosclerosis progression

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It is by now widely recognized that atherosclerosis – with its burden of consequences in cerebro- and cardiovascular diseases – is just a chronic inflammatory process of the arterial wall. A very peculiar, complex and as yet still poorly understood process, upon which hundreds of scientists from several different fields are continuously concentrating their investigative efforts in search of possible leads to therapeutic approaches. Initiation of the disease is given by deposition of lipid in the intimal layers, resulting in endothelial activation and infiltration of blood-derived mononuclear cells. These mature into macrophages, become activated, express scavenger receptors such as SR-A and CD36 and ingest the oxidized lipoprotein accumulating in the lesion. Macrophages thus represent an obvious target for intervention, as they play a crucial role in the progression of the atherosclerotic inflammation. Studies have shown that hypercholesterolaemia can increase monocyte mobilisation from bone marrow into the circulation, and several chemokines and their receptors are involved in the recruitment of blood borne monocytes into the arterial wall. Monocyte-derived macrophages are capable of sustaining their local proliferation, but resident macrophages possibly also participate in progression of the disease. Remarkably, smooth muscle cells can acquire macrophage-like features during atherogenesis, including the ability to uptake lipid, thus becoming a significant proportion of the CD68+ so called ‘foam cells’. Lipid-laden macrophages induce extracellular matrix degradation, while lipid uptake eventually causes their death with formation of a necrotic core. The efficiency in clearance of dead cells by phagocytes (efferocytosis), can also be considered as a determinant of plaque vulnerability. An important feature of macrophages is their great plasticity and functional diversity in response to signals from the plaque microenvironment. Several such ‘signals’ (cholesterol, oxidative stress, hypoxia, cytokines…) can in fact modulate cell differentiation at transcriptional and epigenetic levels, thus altering the balance between the effector vs. reparative functions of macrophages. A whole gamut of specific subsets are thus originated, which appear to be simultaneously present in lesions with proportions that vary according to their location, the disease stage, and the presence of additional cell types such as e.g. dendritic cells. The result is a multiplicity of potential pharmacological targets, representing a major obstacle for the devisement of therapeutic strategies. Experimental approaches have been attempted in diverse directions: e.g. modulating the macrophage phenotype to an anti-inflammatory and resolving state, or blocking pro-inflammatory cytokines that macrophages produce, or alternatively enhancing efferocytosis in order to favour the resolution of inflammation and stabilization of plaques. Blocking monocyte recruitment was proposed in order to hinder the initial steps of atherogenesis. Other treatments were aimed to inhibiting local proliferation of pro-inflammatory macrophages. Specific targeting of macrophages has however to date not yet provided significant, translational results. The present Research Topic collects articles to help unravel the complexity of macrophage behaviour in atherosclerosis and identify innovative pharmacological approaches.

monocytes/macrophages --- inflammation --- foam cell formation --- smooth muscle cells --- atherosclerosis progression

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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Science: general issues --- Neurosciences --- smooth muscle cells (SMCs) --- pericytes --- Alzheimer's disease --- small vessel disease --- vascular cognitive impairment --- mural cells

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Arterial hypertension affects about 1 billion people worldwide and it is the strongest modifiable risk factor for cardiovascular disease and related disability. Since the initial discovery of rare monogenic disorders with large effects, the role of genomics has evolved into large genome-wide association studies detecting common variants with a modest effect size. Similarly, pharmacogenomics has emerged as a new tool for understanding variability in drug response, to maximize efficacy and reduce toxicity. This book presents the most recent advances in the field of genetics and genomics of arterial hypertension and their potential impact on clinical management. The book is a useful tool for clinicians but also to the research community and those who want to be updated in the field.

Research & information: general --- Biology, life sciences --- atrial natriuretic peptide --- T2238C variant --- endothelial dysfunction --- smooth muscle cells contraction --- platelet aggregation --- epigenetics --- cardiovascular diseases --- renin --- low-renin --- hypertension --- mineralocorticoid receptor --- genetics --- aldosterone --- essential hypertension --- blood pressure --- genome-wide association studies --- exome microarray --- next-generation sequencing --- rare variants --- rare-variants association testing --- burden test --- sequence kernel association test --- hypokalemia --- low renin hypertension --- monogenic hypertension --- Liddle syndrome --- SCNN1A --- SCNN1B --- SCNN1G --- non-coding RNA --- micro RNA --- primary aldosteronism --- aldosterone-producing adenoma --- transcriptome profiing --- DNA methylation --- histone modifications --- vascular smooth muscle cells --- endothelial cells --- Kruppel-like factor 15 --- left ventricular hypertrophy --- cardiac hypertrophy --- heart failure --- genetics of left ventricular hypertrophy --- fibromuscular dysplasia --- non atherosclerotic vascular stenosis --- PHACTR1 --- genetic association --- cervical artery dissection --- spontaneous coronary arteries dissection --- CRY1 --- CRY2 --- HSD3B1 --- HSD3B2 --- cardio-tonic steroids --- endogenous ouabain --- adducin --- renal damage --- African American --- ARMC5 --- GRK4 --- CACNA1D --- endocrine hypertension --- atrial natriuretic peptide --- T2238C variant --- endothelial dysfunction --- smooth muscle cells contraction --- platelet aggregation --- epigenetics --- cardiovascular diseases --- renin --- low-renin --- hypertension --- mineralocorticoid receptor --- genetics --- aldosterone --- essential hypertension --- blood pressure --- genome-wide association studies --- exome microarray --- next-generation sequencing --- rare variants --- rare-variants association testing --- burden test --- sequence kernel association test --- hypokalemia --- low renin hypertension --- monogenic hypertension --- Liddle syndrome --- SCNN1A --- SCNN1B --- SCNN1G --- non-coding RNA --- micro RNA --- primary aldosteronism --- aldosterone-producing adenoma --- transcriptome profiing --- DNA methylation --- histone modifications --- vascular smooth muscle cells --- endothelial cells --- Kruppel-like factor 15 --- left ventricular hypertrophy --- cardiac hypertrophy --- heart failure --- genetics of left ventricular hypertrophy --- fibromuscular dysplasia --- non atherosclerotic vascular stenosis --- PHACTR1 --- genetic association --- cervical artery dissection --- spontaneous coronary arteries dissection --- CRY1 --- CRY2 --- HSD3B1 --- HSD3B2 --- cardio-tonic steroids --- endogenous ouabain --- adducin --- renal damage --- African American --- ARMC5 --- GRK4 --- CACNA1D --- endocrine hypertension