Role of Extracellular Vesicles in De Novo Mineralization: An Additional Novel Mechanism of Cardiovascular Calcification (original) (raw)
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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.
Extracellular Vesicles As Mediators of Cardiovascular Calcification
Frontiers in cardiovascular medicine, 2017
Involvement of cell-derived extracellular particles, coined as matrix vesicles (MVs), in biological bone formation was introduced by Bonucci and Anderson in mid-1960s. In 1983, Anderson et al. observed similar structures in atherosclerotic lesion calcification using electron microscopy. Recent studies employing new technologies and high- resolution microscopy have shown that although they exhibit characteristics similar to MVs, calcifying extracellular vesicles (EVs) in cardiovascular tissues are phenotypically distinct from their bone counterparts. EVs released from cells within cardiovascular tissues may contain either inhibitors of calcification in normal physiological conditions or promoters in pathological environments. Pathological conditions characterized by mineral imbalance (e.g., atherosclerosis, chronic kidney disease, diabetes) can cause smooth muscle cells, valvular interstitial cells, and macrophages to release calcifying EVs, which contain specific mineralization-prom...
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.
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
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...
Journal of the American Society of Nephrology, 2004
Patients with ESRD have a high circulating calcium (Ca) ϫ phosphate (P) product and develop extensive vascular calcification that may contribute to their high cardiovascular morbidity. However, the cellular mechanisms underlying vascular calcification in this context are poorly understood. In an in vitro model, elevated Ca or P induced human vascular smooth muscle cell (VSMC) calcification independently and synergistically, a process that was potently inhibited by serum. Calcification was initiated by release from living VSMC of membrane-bound matrix vesicles (MV) and also by apoptotic bodies from dying cells. Vesicles released by VSMC after prolonged exposure to Ca and P contained preformed basic calcium phosphate and calcified extensively. However, vesicles released in the presence of serum did not contain basic calcium phosphate, co-purified with the mineralization inhibitor fetuin-A and calcified minimally. Importantly, MV released under normal physiologic conditions did not calcify, and VSMC were also able to inhibit the spontaneous precipitation of Ca and P in solution. The potent mineralization inhibitor matrix Gla protein was found to be present in MV, and pretreatment of VSMC with warfarin markedly enhanced vesicle calcification. These data suggest that in the context of raised Ca and P, vascular calcification is a modifiable, cell-mediated process regulated by vesicle release. These vesicles contain mineralization inhibitors derived from VSMC and serum, and perturbation of the production or function of these inhibitors would lead to accelerated vascular calcification.
Connective tissue research, 2018
Elevated serum phosphate is one of the major factors contributing to vascular calcification. Studies suggested that extracellular vesicles released from vascular smooth muscle cells significantly contribute to the initiation and progression of this pathology. Recently, we have demonstrated that elevated phosphate stimulates release of extracellular vesicles from osteogenic cells at the initiation of the mineralization process. Here, we used MOVAS cell line as an in vitro model of vascular calcification to examine whether vascular smooth muscle cells respond to high phosphate levels in a similar way and increase formation of extracellular vesicles. Vesicles residing in extracellular matrix as well as vesicles released to culture medium were evaluated by nanoparticle tracking analyses. In addition, using mass spectrometry and protein profiling, protein composition of extracellular vesicles released by MOVAS cells under standard growth conditions and upon exposure to high phosphate was...
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.
Circulation Research, 2011
Rationale: Matrix vesicles (MVs) are specialized structures that initiate mineral nucleation during physiological skeletogenesis. Similar vesicular structures are deposited at sites of pathological vascular calcification, and studies in vitro have shown that elevated levels of extracellular calcium (Ca) can induce mineralization of vascular smooth muscle cell (VSMC)–derived MVs. Objectives: To determine the mechanisms that promote mineralization of VSMC-MVs in response to calcium stress. Methods and Results: Transmission electron microscopy showed that both nonmineralized and mineralized MVs were abundantly deposited in the extracellular matrix at sites of calcification. Using cultured human VSMCs, we showed that MV mineralization is calcium dependent and can be inhibited by BAPTA-AM. MVs released by VSMCs in response to extracellular calcium lacked the key mineralization inhibitor matrix Gla protein and showed enhanced matrix metalloproteinase-2 activity. Proteomics revealed that V...