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Vascular Homeostasis and Inflammation in Health and Disease International Journal of Molecular Sciences Review Vascular Homeostasis and Inflammation in Health and Disease—Lessons from Single Cell Technologies Olga Bondareva * and Bilal N. Sheikh * Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Philipp-Rosenthal-Str. 27, 04103 Leipzig, Germany * Correspondence: [email protected] (O.B.); [email protected] (B.N.S.); Tel.: +49-341-9722912 (B.N.S.) Received: 5 June 2020; Accepted: 30 June 2020; Published: 30 June 2020 Abstract: The vascular system is critical infrastructure that transports oxygen and nutrients around the body, and dynamically adapts its function to an array of environmental changes. To fulfil the demands of diverse organs, each with unique functions and requirements, the vascular system displays vast regional heterogeneity as well as specialized cell types. Our understanding of the heterogeneity of vascular cells and the molecular mechanisms that regulate their function is beginning to benefit greatly from the rapid development of single cell technologies. Recent studies have started to analyze and map vascular beds in a range of organs in healthy and diseased states at single cell resolution. The current review focuses on recent biological insights on the vascular system garnered from single cell analyses. We cover the themes of vascular heterogeneity, phenotypic plasticity of vascular cells in pathologies such as atherosclerosis and cardiovascular disease, as well as the contribution of defective microvasculature to the development of neurodegenerative disorders such as Alzheimer’s disease. Further adaptation of single cell technologies to study the vascular system will be pivotal in uncovering the mechanisms that drive the array of diseases underpinned by vascular dysfunction. Keywords: vasculature; atherosclerosis; single cell technologies; neurodegeneration; inflammation 1. Introduction A healthy and functioning vascular system is critical for ensuring that sufficient nutrients and oxygen reach the ~37 trillion cells in our bodies and the cellular waste products are efficiently removed. To service such a colossal quantity of cells, there is over 100,000 km of vasculature present within our bodies [1], which forms a continuum of vessels from arteries to arterioles, capillaries, venules and veins (Figure1A) [ 2]. Differences in vascular cell phenotypes along the artery to vein axis are referred to as vascular zonation and correspond to unique cellular subtypes in each section of the vasculature (Figure1A) [ 3]. Blood vessels are generally composed of up to three distinct regions or layers: (i) the tunica intima, a monolayer of flat squamous endothelial cells (ECs) that are in direct contact with the blood stream and mounted on a fibro-elastic basement membrane filled with extracellular matrix; (ii) the tunica media, composed of vascular smooth muscle cells (SMCs) and pericytes; and (iii) the tunica adventitia, composed of connective tissue, including fibroblasts and mesenchymal stem cells (MSCs), as well as lymphatic and neural plexi (Figure1B,C) [2]. Int. J. Mol. Sci. 2020, 21, 4688; doi:10.3390/ijms21134688 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 4688 2 of 21 Int. J. Mol. Sci. 2020, 21, 4688 2 of 21 Figure 1. Unique vascular beds in the human body. (A) Blood vessels are zonated and display unique cellular phenotypes and functionality. The 5 major zonation states of vessels are arteries, arterioles, capillaries,Figure 1. Unique venules vascular and veins. beds (B in) Walls the human of arterial body. vessels (A) Blood are typicallyvessels are composed zonated ofand 3 layers:display tunicaunique intima,cellular tunica phenotypes media and and tunica functionality. adventitia. The The 5 intimamajor iszonation the innermost states layerof vessels formed are by arteries, endothelial arterioles, cells thatcapillaries, are in direct venules contact and with veins. the blood.(B) Walls The of intima arterial layer vessels is mounted are typically on the basementcomposed membrane, of 3 layers: which tunica isintima, filled with tunica fibro-elastic media and extracellular tunica adventitia. matrix, The pericytes intima and is the smooth innermost muscle layer cells. formed Media, by the endothelial middle contractilecells that are layer, in direct is composed contact ofwith smooth the blood. muscle The cells intima that layer provide is mounted support andon the flexibility basement to membrane, the vessel. Adventitia,which is filled the outmostwith fibro layer-elastic of connective extracellul tissuear matrix, surrounding pericytes the and vessel, smooth contains muscle fibroblasts, cells. Media, a few the mesenchymalmiddle contractile stem cells layer, and is neurons.composed (C of) Capillaries, smooth muscle the smallest cells that blood provide vessels, support are involved and flexibility in direct to solutethe vessel. exchange Adventitia, with the tissue. the outmost Capillaries layer possess of connective a single layer tissue of ECs surrounding that is surrounded the vessel, by basement contains membranefibroblasts, and a few contains mesenchymal extracellular stem cells matrix and and neurons. pericytes. (C) Capillaries, Pericytes regulatethe smallest the blood permeability vessels, ofare capillariesinvolved andin direct their precisesolute exchange density varies with from the organtissue. to Capillaries organ. (D )possess Neural capillariesa single layer are characterizedof ECs that is bysurrounded an unfenestrated by basement structure membrane and ECs with and tight contains junctions. extrace Neuralllular capillaries matrix and are denselypericytes. populated Pericytes byregulate pericytes the and permeability are often contacted of capillaries by astrocytes and their and precise microglia. density (E) Thevaries heart from is theorgan central to organ. organ in(D) theNeural cardiovascular capillaries system are characterized that pumps bloodby an through unfenestrated the whole structure body, and and its ECs function with is tight supported junctions. by coronaryNeural capillaries arteries. (F )ar Lungse densely possess populated specialized by pericytes vasculature and that are enables often contacted oxygen and by carbon astrocytes dioxide and exchangemicroglia. between (E) The alveoli heart is and the pulmonary central organ capillaries. in the cardiovascular system that pumps blood through the whole body, and its function is supported by coronary arteries. (F) Lungs possess specialized Althoughvasculature the that general enables structure oxygen of and blood carbon vessels dioxide is somewhat exchange conserved between throughoutalveoli and thepulmonary body, each organcapillaries. has unique functions and demands on the vascular system. For instance, arteries and arterioles, the so-called resistance vessels, endure high pressure and shear stress [4]. The pressure and shear stressAlthough gradually the reduce general towards structure the veins, of blood which vessels endure is upsomewhat to 70-fold conserved less pressure throughout than arteries the body, [4]. Dueeach to organ the necessity has unique of withstanding functions and such demands high forces, on the arteries vascular and system. arterioles For possess instance, a thick arteries media and layerarterioles, with numerous the so-called SMCs resistance that provide vessels, elastic endure support high to pressure the vessel and walls. shear Capillaries, stress [4]. onThe the pressure other hand,and shear are the stress smallest gradually and thinnest reduce vessels.towards They the veins, only possess which anendure intima up layer to 70 covered-fold less with pressure basement than membranearteries [4] and. Due are to supported the necessity bypericytes of withstand (Figureing 1suchC). Together, high forces, SMCs arteries and pericytes and arterioles constitute possess the a muralthick cellmedia population layer with that numerous promotes SMCs EC dithatfferentiation, provide elastic maintains support vascular to the vessel tone and walls. regulates Capillaries the , permeabilityon the other ofhand, capillaries are the [ 5smallest,6]. Consistent and thinnest with theirvessels morphology,. They only capillaries possess an are intima the major layer sitescovered of nutrientwith basement and gas membrane exchange. and are supported by pericytes (Figure 1C). Together, SMCs and pericytes constituteBlood vesselsthe mural display cell specializationspopulation that that promotes are closely EC associateddifferentiation, with organmaintains function. vascular For instance,tone and vesselsregulates of thethe kidneypermeability glomerulus of capillaries need to [5,6] interact. Consistent with podocytes with their and morphology, allow filtration capillaries of blood are and the reabsorptionmajor sites of of nutrient fluids. Therefore, and gas exchange. capillary ECs in the kidney are highly fenestrated and permeable [7]. In contrast,Blood thevessels brain display has a highly specializations vulnerable that environment are closely and associated is thus a ffwithorded organ protection function via. theFor blood–braininstance, vessels barrier of (BBB)the kidney that restricts glomerulus the movementneed to interact of cells, with metabolites, podocytes infectiousand allow agentsfiltration and of Int. J. Mol. Sci. 2020, 21, 4688 3 of 21 proteins in and out of the brain [8,9]. Consistently, ECs of the BBB possess highly specialized non-fenestrated vasculature
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