Extracellular Vesicles As Mediators of Cardiovascular Calcification (original) (raw)
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Arteriosclerosis, Thrombosis, and Vascular Biology, 2013
Extracellular vesicles are membrane micro/nanovesicles secreted by many cell types into the circulation and the extracellular milieu in physiological and pathological conditions. Evidence suggests that extracellular vesicles, known as matrix vesicles, play a role in the mineralization of skeletal tissue, but emerging ultrastructural and in vitro studies have demonstrated their contribution to cardiovascular calcification as well. Cells involved in the progression of cardiovascular calcification release active vesicles capable of nucleating hydroxyapatite on their membranes. This review discusses the role of extracellular vesicles in cardiovascular calcification and elaborates on this additional mechanism of calcification as an alternative pathway to the currently accepted mechanism of biomineralization via osteogenic differentiation. (Arterioscler Thromb Vasc Biol. 2013;33:1753-1758.)
Extracellular vesicles in cardiovascular calcification: Expanding current paradigms
The Journal of Physiology, 2016
is an Editorial Board Member of several scientific journals and has authored over 150 manuscripts on cardiovascular pathobiology. Her current research focuses on the mechanisms of vascular calcification and calcific aortic valve disease. This review was presented at the symposium "Extracellular vesicles, exosomes and microparticles in cardiovascular disease", which took place at
Mechanisms of Arterial Calcification: The Role of Matrix Vesicles
European Journal of Vascular and Endovascular Surgery, 2018
Extracellular vesicles are involved in cardiovascular disease; here the earliest phase of vascular calcification is described through an in depth ultra-structural analysis of calcifying matrix vesicles that may represent the unifying motif of the various initiation mechanisms proposed for vascular calcification. These vesicles can be generated locally by dying cells, resident osteoprogenitors or alternatively they may even originate from distant sites that reach the vascular matrix as circulating nucleation complexes. Unravelling their composition and phenotype in normal and pathological conditions will be essential for the development of new therapeutic strategies, in order to prevent and treat vascular calcification. Vascular calcification is related to vascular diseases, for example, atherosclerosis, and its comorbidities, such as diabetes and chronic kidney disease. In each condition, a distinctive histological pattern can be recognised that may influence technical choices, possible intra-operative complications, and procedure outcomes, no matter if the intervention is performed by open or endovascular means. This review considers the classification and initiating mechanisms of vascular calcification. Dystrophic and metastatic calcifications, Monckeberg's calcification, and genetic forms are firstly outlined, followed by their alleged initiation mechanisms; these include (a) ineffective macrophage efferocytosis; (b) ectopic osteogenesis driven by modified resident or circulating osteoprogenitors. As in physiological bio-mineralisation, active calcification starts with the deposition of cell derived matrix vesicles into the extracellular matrix. To substantiate this belief, an in depth ultra-structural documentation of hydroxyapatite crystal deposition on such vesicles is provided in an ex-vivo human vascular cell model. Revealing the vesicle composition and phenotype in normal and pathological vascular conditions will be essential for the development of new therapeutic strategies, in order to prevent and treat vascular calcification.
2020
BackgroundFewer than 50% of patients develop calcification of both atherosclerotic plaques and aortic valves, implying differential pathogenesis. While circulating extracellular vesicles (EVs) act as biomarkers of cardiovascular diseases, tissue-entrapped EVs associate with early mineralization, but their contents, function, and contributions to disease remain unknown.ResultsGlobal proteomics of human carotid artery endarterectomies and calcified aortic valves from a total of 27 donors/patients revealed significant over-representation of proteins with vesicle-associated pathways/ontologies common to both diseases. We exploited enzymatic digestion, serial (ultra)centrifugation and OptiPrep density-gradient separation to isolate EV populations from diseased arteries and valves. Mass spectrometry found 22 EV marker proteins to be highly enriched in the four least-dense OptiPrep fractions while extracellular matrix proteins predominated in denser fractions, as confirmed by CD63 immunogo...
Role of Extracellular Vesicles in De Novo Mineralization
Arteriosclerosis, Thrombosis, and Vascular Biology, 2013
Extracellular vesicles are membrane micro/nanovesicles secreted by many cell types into the circulation and the extracellular milieu in physiological and pathological conditions. Evidence suggests that extracellular vesicles, known as matrix vesicles, play a role in the mineralization of skeletal tissue, but emerging ultrastructural and in vitro studies have demonstrated their contribution to cardiovascular calcification as well. Cells involved in the progression of cardiovascular calcification release active vesicles capable of nucleating hydroxyapatite on their membranes. This review discusses the role of extracellular vesicles in cardiovascular calcification and elaborates on this additional mechanism of calcification as an alternative pathway to the currently accepted mechanism of biomineralization via osteogenic differentiation.
Roles and Regulation of Extracellular Vesicles in Cardiovascular Mineral Metabolism
Frontiers in Cardiovascular Medicine
Cardiovascular calcification is a multifaceted disease that is a leading independent predictor of cardiovascular morbidity and mortality. Recent studies have identified a calcification-prone population of extracellular vesicles as the putative elementary units of vascular microcalcification in diseased heart valves and vessels. Their action is highly context-dependent; extracellular vesicles released by smooth muscle cells, valvular interstitial cells, endothelial cells, and macrophages may promote or inhibit mineralization, depending on the phenotype of their originating cells and/or the extracellular environment to which they are released. In particular, emerging roles for vesicular microRNAs, bioactive lipids, metabolites, and protein cargoes in driving this pro-calcific switch underpin the necessity of innovative strategies to employ next-generation sequencing and omics technologies in order to better understand the pathobiology of these nano-sized entities. Furthermore, a recent body of work has emerged that centers on the novel re-purposing of extracellular vesicles and exosomes as potential therapeutic avenues for cardiovascular calcification. This review aims to highlight the role of extracellular vesicles as constituents of cardiovascular calcification and summarizes recent advances in our understanding of the biophysical nature of vesicle accumulation, aggregation, and mineralization. We also comprehensively discuss the latest evidence that extracellular vesicles act as key mediators and regulators of cell/cell communication, osteoblastic/osteoclastic differentiation, and cell/matrix interactions in cardiovascular tissues. Lastly, we highlight the importance of robust vesicle isolation and characterization when studying these phenomena, and offer a brief primer on working with cardiovascular applications of extracellular vesicles.
Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques
Nature materials, 2016
Clinical evidence links arterial calcification and cardiovascular risk. Finite-element modelling of the stress distribution within atherosclerotic plaques has suggested that subcellular microcalcifications in the fibrous cap may promote material failure of the plaque, but that large calcifications can stabilize it. Yet the physicochemical mechanisms underlying such mineral formation and growth in atheromata remain unknown. Here, by using three-dimensional collagen hydrogels that mimic structural features of the atherosclerotic fibrous cap, and high-resolution microscopic and spectroscopic analyses of both the hydrogels and of calcified human plaques, we demonstrate that calcific mineral formation and maturation results from a series of events involving the aggregation of calcifying extracellular vesicles, and the formation of microcalcifications and ultimately large calcification areas. We also show that calcification morphology and the plaque's collagen content-two determinants...
Calcifying Matrix Vesicles and Atherosclerosis
BioMed Research International
Artery calcification is a well-recognized predictor of late atherosclerotic complications. In the intima media, calcification starts with apoptosis of vascular smooth muscle cells (VSMCs) and the release of calcifying matrix vesicles with diameter of 0.5–15 μm that can be observed microscopically. In complicated plaques, calcification is generally less frequent. Calcifying vesicles are released by proatherosclerotic VSMCs into the collagen-rich matrix. The vesicles can penetrate into the intima media and protrude into the arterial lumen and thereby may represent a potential cause of atherothrombosis. In calcified fibrolipid plaques, the rate of calcification is increased but is followed with healing of a lesion rupture and exhibited by further erosion and/or intimal thickening. Generally, calcification directly correlates with the apoptosis of VSMCs and macrophages accompanied by the release of osteogenic matrix vesicles. This is a hallmark of atherosclerosis-related apoptosis of VS...