Abstract
Extracellular vesicles (EVs) have received considerable attention in biological and clinical research due to their ability to mediate cell-to-cell communication. Based on their size and secretory origin, EVs are categorized as exosomes, microvesicles, and apoptotic bodies. Increasing number of studies highlight the contribution of EVs in the regulation of a wide range of normal cellular physiological processes, including waste scavenging, cellular stress reduction, intercellular communication, immune regulation, and cellular homeostasis modulation. Altered circulating EV level, expression pattern, or content in plasma of patients with cardiovascular disease (CVD) may serve as diagnostic and prognostic biomarkers in diverse cardiovascular pathologies. Due to their inherent characteristics and physiological functions, EVs, in turn, have become potential candidates as therapeutic agents. In this review, we discuss the evolving understanding of the role of EVs in CVD, summarize the current knowledge of EV-mediated regulatory mechanisms, and highlight potential strategies for the diagnosis and therapy of CVD. We also attempt to look into the future that may advance our understanding of the role of EVs in the pathogenesis of CVD and provide novel insights into the field of translational medicine.
1. Introduction
Cardiovascular diseases (CVD), including coronary heart disease, heart failure, stroke, congenital heart disease, rhythm disorders, and hypertension, remain the leading causes of morbidity and mortality around the world [1]. In the United States, the prevalence of CVD in adults 20years of age and older is 48.0% overall (121.5 million in 2016) (NHANES 2013–2016) [2]. The prevalence of CVD increases with age in both males and females. In 2016, approximately 161,438 (19.2%) Americans who were <65 years old died of CVD; 306,638 (36.5%) of the deaths attributable to CVD occurred before the age of 75 years [2]. In 2016, the Chinese Cardiovascular Disease Report estimated that 290 million (21%) Chinese had CVD, the leading cause of mortality (61%) [3]. Globally, CVD produces immense health and economic burden [4–6]. In the United States, the cost of informal caregiving for patients with CVD is projected to increase from $616 billion in 2015 to $1.2 trillion in 2035 [7]. Thus, increasing the efficacy in the prevention and treatment of CVD has a huge potential in improving global health outcome and decreasing financial burden [8,9].
Cell-to-cell communication, a key process in multicellular organisms, is required to guarantee proper coordination among the different cell types within tissues and thus, fundamental for the functioning of biological systems. There are multiple modes of intercellular communication, including soluble factors, tunneling nanotubes, and extracellular vesicles (EVs), which allow the transfer of surface molecules or cytoplasmic components from one cell to another [10–12]. Among them, EVs have received a lot of attention in biological and clinical research due to their ability to mediate cell-cell crosstalk. EVs originate from diverse subcellular compartments of most eukaryotic cells and are released into the extracellular space in normal and disease states [13–15]. EVs are categorized as exosomes, microvesicles, and apoptotic bodies, according to their abundance, size, and composition. They contain different materials, which include many functional molecules, such as microRNAs (miRNAs), messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), proteins, DNA fragments, and lipids [12–14]. Those components can be delivered from the cell of origin to a recipient cell, whether the recipient cell is in the vicinity or distant from the cell of origin. The transferred molecules are potentially capable of eliciting changes in function and gene expression in the recipient cell. Numerous studies have shown that EVs may serve as biomarkers for the diagnosis and treatment of diseases, including cardiovascular diseases [16–18]. In this review, we discuss the evolving understanding of the role of EVs in CVD, summarize the current knowledge of EV-mediated regulatory mechanisms, and highlight potential strategies for the diagnosis and treatment of CVD, and also attempt a look into the future. These may advance our understanding of the role of EVs in CVD and provide novel insights into the field of translational medicine.
1.1. EV classification
EVs were first described in 1967; this subcellular fraction, identified by electron microscopy, consists of small vesicles, with a diameter between 20 and 50 nm, and termed “platelet dust” from activated platelets [19]. EV is an umbrella term for all types of vesicles released from prokaryotic and eukaryotic cells. Currently, there is an ongoing debate on the classification of EVs with some investigators having preference to classify the EVs according to their source, such as endothelial cell-derived EVs, vascular smooth muscle cell-derived EVs, cardiac fibroblast-derived EVs, macrophage-derived EVs, etc. [20–22]. However, this manner of classification for EVs does not reflect the character of a particular EV. Moreover, there is also some controversy on the nomenclature and sizes of the different types of vesicles. Therefore, in 2014 and updated in 2018, the International Society for Extracellular Vesicles (ISEV) provided some standards in the classification of EVs, based on various morphological, biochemical, and biogenic parameters [23,24]. However, until now, there is no consensus on the nomenclature of EVs that define the cellular origin or classification of EVs once they have been secreted or shed from the cell of origin [25]. For this reason, the term “extracellular vesicle” is suggested by the ISEV as a generic name for all secreted vesicles, and also as a keyword in publications [26]. Recent reviews have categorized EVs into three groups [27–29]: exosomes, microvesicles, and apoptotic bodies.
1.1.1. Exosomes
Exosomes are a homogenous population of EVs derived from the endocytic compartment. These cell-derived nanovesicles, ranging in size between 30 and 100 nm in diameter, are surrounded by a lipid bilayer [30,31]. Usually, exosomes are able to float on a sucrose gradient at a density of 1.13—1.19 g/mL. Exosomes typically display a cup-like shape when observed by transmission electron microscopy, but this may be an artifact [32]. Their biogenesis is initiated by the inward budding of multi-vesicular endosomes. The transmembrane proteins are endocytosed and trafficked to early endosomes, which invaginate to generate intraluminal vesicles and form multivesicular bodies (MVBs). Then, the MVBs can either fuse with the plasma membrane and the intraluminal vehicles are released as exosomes into the extracellular space (Fig. 1); the intraluminal vesicles can also fuse with lysosomes for eventual degradation [33,34].
Fig. 1.
Biogenesis and transport of extracellular vesicles (EVs). EVs can be classed as exosomes, microvesicles (ectosomes, microparticles), and apoptotic bodies based on their different mechanisms of biogenesis multivesicular bodies (MVBs), which fuse with the plasma membrane, and the intraluminal vehicles are released as exosomes into the extracellular space. Microvesicles are generated directly from plasma membrane budding. EVs are taken up by recipient cells by several mechanisms including endocytosis, phagocytosis, pinocytosis, membrane fusion, or receptor-mediated endocytosis.
Exosomes are released from cells via a constitutive or inducible mechanism, depending on the cell type of origin [35]. In general, exosomes are wrapped by a phospholipid bilayer, enriched with sphingomyelin, ceramide, and cholesterol [36,37]. The biochemical composition of exosomes depends on the cell source. Cells release subpopulations of exosomes with different sizes, compositions, and molecular and biological properties [38]. The mechanisms proposed for their release, include Rab GTPases (Rab11/35, Rab27), tetraspanins, and SNAREs (soluble N-ethylmaleimide-sensitive attachment protein receptors) complex [39–41]. Tetraspanins, including CD9, CD63, CD81, CD82, and CD151, exist in released exosomes and accumulate in plasma membrane endosomes and microdomains [42,43]. In the plasma membrane, tetraspanins form tetraspanin-enriched microdomains (TEMs). TEMs are involved in many biological process, including exosome biogenesis, exosome internalization, selection of exosome cargo, and antigen presentation [44,45]. In addition to tetraspanins and lipids, there are other components, such as cargos, in EVs, including sorting proteins (e.g., Alix, clathrin, TSG101), related to MVB biogenesis, membrane proteins (e.g., Rab GTPase and annexins) regulating exosome docking and membrane fusion, cytoskeleton proteins (e.g., actin, tubulin), inflammatory cytokines (e.g., IL-10, transforming growth factor-β [TGF-β]), metabolic enzymes (e.g., pyruvate kinase, α-enolase), as well as different RNA species (e.g., mRNA, miRNA, lncRNA), and DNAs [12–14,46,47]. Via the above cargos, exosomes can exert their vast and varied physiological functions, through either direct interaction with surrounding cells, where they are generated, or transported to distant recipient cells by their release into the circulatory fluid system.
1.1.2. Microvesicles
Microvesicles, also known as microparticles, ectosomes, and membrane particles, represent a more heterogeneous population than exosomes. They are a class of EVs typically ranging in size between 100 and 1000 nm in diameter [48,49]. Although exosomes are generally smaller than microvesicles, their sizes may overlap. Microvesicles float on sucrose gradient at a density of 1.04–1.07 g/mL. They have been characterized predominantly, as products of platelets, red blood cells, and endothelial cells.
In addition to the size and density differences, microvesicles differ from exosomes by their mechanisms of release and biogenesis. Microvesicles are derived from activated or apoptotic cells through outward budding and fission of membrane vesicles from the plasma membrane [50,51]. In response to stimuli, outward blebbing may be dependent on various enzymes and mitochondrial or calcium signaling. Microvesicle shedding shares a similar process with virus budding. Moreover, microvesicles may be assembled selectively in the lipid-rich microdomains of the membrane, including lipid rafts or caveolae [52,53]. In mammals, microvesicles are released from almost all cell types, including blood cells (e.g., platelets, erythrocytes, leukocytes), vascular smooth muscle cells (VSMCs), and endothelial cells [54–56]. The release can be observed within a few seconds after stimulation [41].
Microvesicles reflect the nature and the activation state of the parent cell and are identified by the expression of phosphatidylserine on their surfaces, which is indicative of their release from apoptotic or activated cells. The preferential binding of annexin to phosphatidylserine can be used to detect the exposed phosphatidylserine on the surface of apoptotic cells and phosphatidylserine-positive microvesicles subclass [57,58]. However, not all microvesicles express phosphatidylserine, and therefore, certain microvesicle populations fail to bind annexin V [59], suggesting that some microvesicles might be formed by other undetermined mechanisms. Microvesicles have markers different from those of exosomes, e.g., tryptophanyl-TRNA synthase 1 and C1q [41]. It should be noted that there are some similarities between exosomes and microvesicles. For example, both contain adhesion molecules, membrane receptors, tissue factors, cytoskeletal proteins, chemokines, various enzymes and cytokines, as well as DNAs and RNAs (mRNA, microRNA). Microvesicles can carry nuclear proteins that originate from apoptotic cells [60,61].
1.1.3. Apoptotic bodies
Apoptotic bodies, generally ranging in size from 1 to 5 μM in diameter (approximately the size of platelets), are produced from the plasma membrane as blebs when cells undergo apoptosis. Apoptotic bodies are closed structures and are larger than exosomes and microvesicles. They float on a sucrose gradient at a density between 1.16 and 1.28 g/mL, overlapping with the density of exosomes. Apoptotic membrane blebbing is a late stage of programmed cell death that is controlled by caspase-mediated cleavage, and subsequent activation of Rho-associated protein kinases [62,63]. They are characterized by the presence of externalized phosphatidylserine and permeable membrane. Apoptotic bodies contain several intracellular fragments and cellular organelles, including histones, DNA fragments, degraded proteins, nuclear fractions, coding RNAs, noncoding RNAs, and DNAs, similar to those inside microvesicles [62–65].
Apoptotic bodies may provide an easier system for cellular clearance, since they are smaller than cells and are, therefore, easier to phagocytose [66]. Apoptotic bodies have been suggested to act by “dispatching suicide notes” on the surrounding environment. Indeed, apoptotic body membranes show increased permeabilization by releasing proteins into the microenvironment during the early stages of apoptosis. In turn, the surrounding cells, which lose their membrane integrity, affect apoptotic cells during secondary necrosis [67]. However, the exact function of apoptotic bodies is still unclear. Moreover, little is known about their molecular composition. Therefore, the role of apoptotic bodies in the pathophysiology of disease is not covered in this review.
As stated above, because of the difficulties in the isolation and detection of EVs, their classification cannot be rigorously determined in most settings at this time. The ISEV has provided some standards to classify EVs, according to various morphological, biochemical, and biogenic parameters. EVs continue to be classified into exosomes, microvesicles, and apoptotic bodies [27–29]. With the improvement of technologies, more criteria for the classification for EVs could be added, such as refractive index, potential energy, and chemical composition [68,69].
1.2. Isolation of EVs
The isolation and purification of EVs have attracted attention because of their potential to aid in the diagnosis and treatment of a broad range of disorders. Today, diverse biochemical and biophysical properties of EVs are used in their isolation, including buoyant density, size, shape, charge, and surface composition [24,70–72]. The most widely used method for EV isolation is differential centrifugation, originally developed by Johnstone et al. for the separation of EVs in reticulocyte tissue culture fluid and subsequently optimized by Théry et al. [32,73]. Differential centrifugation can separate vesicle particles based on their size and density by sequentially increasing the centrifugal force to pellet cells and debris (<1500 g), large EVs (10,000–20,000 g), and small EVs (100,000–200,000 g) [74]. This method is widely used for various biological samples and is considered the standard for isolating EVs.
In addition to differential centrifugation, other methods have been developed for the isolation of EVs. These include density gradient centrifugation, size-exclusion chromatography, ultrafiltration, immunocapture, and various precipitation-based methodologies, using different reagents [24,75]. In theory, EVs may be isolated based solely on their physicochemical properties, because they are larger than protein fractions but smaller than whole cells, more dense than the lipid fractions, and have a defined density range [76]. However, the above methods have not reached the ultimate goal of having homogeneous EV subpopulations and precise study of their targets. All of these approaches have their respective limitations, which should be taken into consideration; technical standards are not yet fully established [77]. Some researchers have proposed that the choice of a specific isolation method may depend not only on the type of sample (for example, proteinuric urine or non-proteinuric urine) but also on the type of downstream analyses used for “omics” characterization (e.g., transcriptomics or proteomics) [28]. Furthermore, currently, most researchers perform one or more other methods after the main steps, such as washing in EV-free buffer, ultrafiltration, and further purification by density gradient [78]. Thus, currently, there is no ideal method to isolate relatively pure samples that only contain EVs. Further improvements of the above or new methods to isolate EVs are needed.
2. Biological functions of EVs
Initially, EVs were thought to be merely inert cellular debris, also known as “cell dust,” with no biological significance. However, subsequent studies indicated that EVs play important roles in the regulation of a wide range of normal cellular physiological processes, such as waste scavenging, cellular stress reduction, intercellular communication, immune regulation, and cellular homeostasis modulation.
2.1. Waste scavenging
Waste scavenging is the original biological function ascribed to EVs. In 1967, Peter Wolf found that fresh plasma, devoid of intact platelets, contained minute particulate materials, named as platelet-dust, which were obtained by ultracentrifugation [19]. Moreover, he also found that these materials are rich in phospholipids with coagulant properties, resembling those of platelet factor 3. The “platelet-dust” was distinguishable from intact platelets, red cell stroma, and chylomicra [19]. In 1981, Trams et al. found exfoliated membrane vesicles with 5′-nucleotidase activity from several normal and neoplastic cell lines [79]. They coined the word “exosome” to describe EVs with diameters of 500–1000 nm [79]. Subsequently, two independent studies found that transferrin receptors, associated with 50 nm vesicles, were jettisoned from maturing blood reticulocytes into the extracellular space [80,81]. Despite these reports, EVs were still considered as cellular debris, resulting from cell damage or dynamic plasma membrane shedding. Thus, waste scavenging has always been thought as an essential biological function of EVs.
2.2. Cellular stress reduction
Reducing cellular stress is another primary biological function of EVs. The release of EVs varies depending upon different stress conditions, such as endoplasmic reticulum stress, metabolic stress, thermal stress, and oxidative stress. Collett et al. found that endoplasmic reticulum stress stimulates the release of EVs carrying danger-associated molecular pattern molecules (DAMPs). DAMPs may contribute to the increased systemic maternal inflammatory response characteristic of pre-eclampsia [82]. Under conditions of metabolic stress, circulating adipocyte-derived EVs are increased, which act as “find-me” signals to promote macrophage migration and activation [83]. Genotoxic stress increases exosome release from multiple myeloma cells [84]. Thermal and oxidative stresses enhance the release of exosomes in leukemia/lymphoma T and B cells [85].
The proteome composition of EVs is affected by environmental physicochemical stress caused by heat, DNA damaging factors, and oxidation [86]. de Jong et al. exposed endothelial cells to different cellular stresses, including hypoxia, tumor necrosis factor-α (TNF-α), high glucose and mannose concentrations, and then compared mRNA and protein content of exosomes produced by these cells. They identified 1354 proteins and 1992 mRNAs in endothelial cell-derived exosomes, and found that hypoxia and endothelial activation are reflected in RNA and protein exosome composition, and that exposure to high sugar concentrations alters exosome protein composition only to a minor extent, and does not affect exosome RNA composition [87].
While stress affects the proteome composition of EVs, EVs can reduce different types of cellular stress. For example, exosomes from adipose-derived mesenchymal stem cells (MSC) prevent cardiomyocyte apoptosis induced by oxidative stress [88]. EVs from human umbilical cord MSCs can: (1) alleviate oxidative injury and epithelial-mesenchymal transformation in renal epithelial cells [89]; (2) alleviate rat hepatic ischemia-reperfusion injury by suppressing oxidative stress [90]; and (3) repair cisplatin-induced acute kidney injury in rats and NRK-52E cell injury, by ameliorating oxidative stress and cell apoptosis, and promoting cell proliferation, in vivo and in vitro [91]. Exosomes from human platelet-rich plasma prevent apoptosis-induced glucocorticoid-associated endoplasmic reticulum stress in the rat femoral head [92].
2.3. Intercellular communication
Communication between and among cells is necessary for proper development and function. One of the important biological functions of EV is to promote intercellular communication. The transfer and function of miRNAs in EVs have attracted considerable attention in the pathogenesis of CVDs. For example, mesenchymal stromal cell-derived exosomes attenuate myocardial ischemia-reperfusion injury in mice, by the shuttling of miR-182, which modulates the polarization of macrophages [93]. Another study found that miR-93-5p-enhanced adipose-derived stromal cell-derived exosomes prevent acute myocardial infarction-induced myocardial damage, by inhibiting autophagy and inflammation [94]. Activated macrophages secrete miR-155-enriched exosomes, which suppress fibroblast proliferation and promote fibroblast inflammation, during cardiac injury [95]. We have also reported that MSC-derived EVs, via miR-210, improve the function of infarcted hearts, by promoting angiogenesis [96]. In addition to miRNAs, a number of studies have shown that mRNAs (protein-coding RNA), lncRNAs, circRNAs, and DNA fragments are also packaged in EVs. These contents can be delivered to target cells and modulate their biological function by promoting or repressing target gene expression [97–99]. Our previous study found that there are at least 16,434 genomic DNA fragments in the EVs from human plasma, as determined by Illumina Solexa Sequencing Technology. Some of the genomic DNA fragments in EVs could be homologously or heterologously transferred from donor cells to recipient cells, and increase gDNA-coding mRNA, protein expression, and function (e.g., AT1 receptor) [100]. Moreover, mitochondrial DNA (mtDNA) can also be carried by EVs. In chronic heart failure patients, plasma-derived exosomes carry mtDNA, and trigger an inflammatory response, via the TLR9-NF-κB pathway; the inflammatory effect is closely related to exosomal mtDNA copy number [101].
Proteins are other important cargos transferred by EVs. The first evidence for this was obtained in platelets in which functional tissue factor was transferred via microvesicles to monocytes and other cells; platelet tissue factor initiates intravascular coagulation [102]. Other proteins, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and TGF-β, can also be transferred by EVs to other cells [103,104]. Other proteins in EVs, such as receptors, protein kinases, pathway signaling molecules, and cell adhesion molecules, can be directly transferred from one cell to another [105–107]. For example, functional receptor tyrosine kinases (RTKs) can be transported to monocytes by cancer cell-derived exosomes, subsequently stimulating the mitogen-activated protein kinase (MAPK) pathway in the recipient cell. This leads to inactivation of apoptosis-related caspases, which promotes carcinogenesis and progression [108]. Wnt signaling plays an important role in the fibrotic processes in the heart. Exosomes containing Wnt proteins, such as Wnt-3a and Wnt-5a, contribute to cardiac fibrosis by activating profibrotic Wnt pathways in cardiac fibroblasts. This may be a novel mechanism of spreading profibrotic signals in the heart [109]. EVs are also enriched in lipids, such as cholesterol, glycolipids, sphingolipids, glycerophospholipids, and ceramide [110]. Exosomes display the original lipids organized in a bilayer membrane and along with the lipid carriers, such as fatty acid binding proteins that they contain; exosomes transport bioactive lipids [111].
2.4. Immune regulation
EVs play vital roles in the regulation of inflammatory response, such as antigen presentation, immune modulation, complement activation, and autoimmunity, via various mechanisms [112–114]. A comprehensive proteomic analysis showed that cytokines, chemokines and chemokine receptors, such as IL10, HGF, LIF, CCL (chemokine ligand) 2, VEGFC, C-reactive protein (CRP), and CCL20, are found in different cell-derived EV proteomes [115,116]. EVs can promote and suppress immune responses by delivering inflammatory factors and receptors. For example, EVs released from inflamed endothelial cells are enriched with a mixture of inflammatory markers, such as chemokines, and cytokines, intercellular adhesion molecule (ICAM)-1, CCL-2, interleukin-6 (IL-6), IL-8, CXCL-10, CCL-5, and TNF-α. These EVs establish a targeted crosstalk between endothelial cells and monocytes, reprogramming them toward a pro- or anti-inflammatory phenotype [117]. Platelet EVs exert a strong immunomodulatory activity on smooth muscle cells. In particular, platelet-derived EVs induce a switch toward a proinflammatory phenotype, stimulating vascular remodeling via P-selectin, integrin αIIbβ3, CD40L, CX3CR1, and IL-6 [118]. Studies in humans have also demonstrated a regulatory role of EVs on the inflammatory response. In healthy subjects, plasma cytokines (TNF-α, IL-1β, IL-8, IL-6, IL-1ra, IL-10) and chemokines (chemoattractant protein 1 [MCP-1] and RANTES) are elevated in exosomes of HIV-infected alcohol drinkers and cigarette smokers [119]. EVs from patients with inflammatory bowel disease contain significantly higher mRNA and protein levels of IL-6, IL-8, IL-10, and TNF-α than EVs from healthy controls. These EVs have proinflammatory effects on colonic epithelial cells and macrophages [120]. These reports show that cytokines and chemokines may be packaged in different cell-derived EVs at varying degrees in different subjects. However, it should be noted that EVs modulate immune responses not only by stimulating the release of pro-inflammatory cytokines but also through the release of anti-inflammatory mediators [121,122].
EVs are also involved in immuno-regulation by directly modulating various immune cells. EVs can modulate the function of many immune cell types, including T and natural killer (NK) cells. For example, EVs from MSCs can prevent the onset of contact hypersensitivity by inhibiting Tc1 and Th1 immune responses and expansion of regulatory T cells [123]. Tumor-derived EVs inhibit NK cell function by decreasing the expression of NKG2D, CD107a, TNF-α, and INF-γ, and impairing glucose uptake [124]. There are also differential and transferable regulatory effects of EVs on T, B, and NK cell functions [125]. However, the most effective regulatory activity of EVs is conferred through antigen-presenting cells (APC), either by binding to the cell surface or by internalization [126]. Human B cell-derived EVs could effectively present MHC class II (MHC-II) peptide complexes to CD4 T cells in vitro [126–128]. Mature dendritic cells (DC), mouse bone marrow-derived DCs, human primary monocyte-derived DCs, and DC cell lines have all been reported to release EVs, which exert either immune-inhibitory or -stimulatory function, depending upon the status of the donor DC [127]. Indirect antigen presentation for a subset of natural HLA class II ligands can be transferred also between CD4 T cells by EVs [128].
EVs are likely to participate in the formation of immune complexes, based on their autoantigen content. For example, B cell-derived exosomes carry CD23, low affinity IgE receptors, and IgE antigen complexes, increasing specific T cell proliferation and specific IgG production [129]. B cell-derived exosomes also express high levels of MHC class I, MHC class II, and CD45RA (B220), as well as components of the B cell receptor complex, namely, surface Ig, CD19, and the tetraspanins CD9 and CD81 [130]. DC-derived EVs carry MHC class I and class II/peptide complexes and are able to prime other immune system cell types and activate an antitumor immune response [131].
2.5. Cellular homeostasis modulation
Cellular homeostasis is a critical process in the development and maintenance of life. The most important aspect of the maintenance of cellular homeostasis is to keep the dynamic balance between cell loss and cell gain. In the same type of cell, EVs from different conditions may be involved in the modulation of cellular homeostasis via various mechanisms. For example, the cellular homeostasis of cardiomyocytes is regulated by the balance of EV-associated cellular proliferation, apoptosis, and autophagy. Microvesicles derived from human umbilical vein endothelial cells (HUVECs) treated with hypoxia/reoxygenation, which is used to mimic ischemia/reperfusion injury, promote apoptosis in H9c2 cardiomyocytes, leading to myocardial damage [132]. By contrast, EVs from the serum of healthy human volunteers increase the proliferation of H9C2 cardiomyocytes by upregulating miR-17-3p/TIMP3, a potential therapeutic target for cardiac rehabilitation and repair [133]. Exosomes derived from MSCs have been shown to reduce myocardial ischemia/reperfusion injury by the induction of cardiomyocyte autophagy [134]. MSC-derived exosomes can attenuate diabetic nephropathy in a rat model of streptozotocin-induced diabetes mellitus, by induction of autophagy, related to an increase of LC3/Beclin-1 and a decrease in mTOR expressions [135]. However, there is a contradictory report showing that exosomes from human MSCs reduce cardiac ischemia/reperfusion injury by the inhibition, not promotion, of apoptosis and autophagy, by up-regulation of Bcl-2/mTORC1 and down-regulation of Traf6 [136].
3. EVs and cardiovascular diseases
As mentioned above, EVs are involved in physiological processes that are associated with intercellular communication. In the cardiovascular system, EVs could be produced by a variety of cells such as cardiomyocytes, VSMCs, endothelial cells, fibroblasts, immune cells, platelets, leukocytes, and erythrocytes [137]. These EVs have been found to play vital roles in both cardiovascular physiological and pathological conditions, which involve the modulation of specific receptor or signal transduction, inflammatory response, proteolytic enzymes, reactive oxygen species, blood coagulation, and other mechanisms.
3.1. EVs and atherosclerosis
Atherosclerosis is one of the leading causes of mortality from CVD, which leads to stroke, myocardial infarction, and death. Atherosclerosis is characterized by the accumulation of lipid-laden cells beneath the endothelium and formation of atheroma, or fatty deposits, in the intima of the arteries. Several studies have shown that EVs participate in the key processes of atherosclerosis, including VSMC proliferation and migration, endothelial dysfunction, calcium-phosphorus balance, cellular lipid metabolism, and vascular wall inflammation, ultimately resulting in vascular remodeling [110,138].
3.1.1. EVs in atherosclerosis
Emerging studies have highlighted the role of EVs during the initiation and progression of atherosclerotic lesions. Increased levels of circulating EVs are found in patients with atherosclerosis; moreover, the EV contents in atherosclerosis are altered [110,139]. The circulating EVs in atherosclerosis originate from several cells. For example, total-, monocyte-, endothelial-, erythrocyte-, and tissue factor-positive cell-derived microvesicles are increased in patients with familial hypercholesterolemia [140]. Patients with metabolic syndrome have increased levels of microvesicles derived from platelets, erythrocytes, and endothelial cells [141]. EVs are increased not only in the circulation but also in the atherosclerosis plaques [142]. Furthermore, transmission electron microscopy also showed increased number of EVs in smooth muscle cells and endothelial cells from humans with atherosclerosis [143].
The increased EV levels in the circulation and atherosclerotic plaques have clinical implications [144–146]. Thus, endothelial microparticles in eccentric type II or multiple irregular lesions (high-risk) are 2.5-fold higher than in type I or concentric (low-risk) lesions; lesions with thrombi have threefold higher endothelial microparticles than those without thrombi. Interestingly, mild stenosis (>20% to <45%) has threefold higher endothelial microparticles than more severe stenosis (>45%), and fivefold higher than those without stenosis [139]. Even in subjects with ultrasound evidence of subclinical atherosclerosis, leukocyte-derived microparticles, identified by affinity for CD11a, are also increased, which predict subclinical atherosclerosis burden in asymptomatic subjects [144]. Furthermore, elevated EVs are associated with the plaque vulnerability. A prospective, case-controlled study showed that circulating endothelial microparticles are higher in patients with acute coronary syndromes than those with stable angina [145]. Leukocyte-derived microparticle levels are also higher in patients with unstable plaques than those with stable plaques, suggesting an association between plasma levels of leukocyte-derived microparticles and plaque vulnerability in asymptomatic patients with high-grade carotid stenosis [146]. The profile of nucleic acids (mRNAs, miRNAs, lncRNAs) and protein contents are also altered in EVs in patients with and animal models of atherosclerosis [14,110,147,148]. Thus, EVs and their contents may serve as potential diagnostic and prognostic biomarkers for atherosclerotic diseases [137,149].
3.1.2. Mechanism of EVs involved in atherosclerosis
3.1.2.1. EVs and VSMC proliferation/migration
The proliferation and migration of VSMCs from the tunica media to the subendothelial region lead to vessel thickening and subsequent occlusion [150]. EVs are involved in cell proliferation. EVs exert different effects within the same pathophysiological process which may be related to their different cellular origins [151–155]. Thus, platelet-derived EVs increase VSMC proliferation and migration by relying on their interactions with CD40- and P-selectin [118]. Platelet-derived EVs also increase flow-resistant monocyte adhesion to VSMCs and induce a switch toward a pro-inflammatory phenotype, stimulating vascular remodeling [118]. Exosomes derived from M1 macrophages, by delivering miR-222 into VSMCs, accelerate VSMC proliferation and migration, leading to aggravation of neointimal hyperplasia, following carotid artery injury in mice [154]. Macrophage foam cells in atherosclerotic patients generate more EVs than normal macrophages which promote VSMC adhesion and migration, by regulating the actin cytoskeleton and focal adhesion pathways [155]. However, thrombin inhibits VSMC proliferation by stimulating platelet-derived exosomes [153]. Exosomes from MSCs also inhibit VSMC proliferation and migration in vitro and neointimal hyperplasia in vivo, by transferring miR-125b to VSMCs [152].
3.1.2.2. EVs and vascular inflammation
Studies in humans have shown an association between EVs and vascular inflammation [118,156–160]. ICAM-1 expression in EVs, isolated from unstimulated and TNF-α-stimulated vascular endothelial cells of patients with coronary heart disease, is markedly increased, relative to those obtained from healthy controls [157]. The injection of microparticles from metabolic syndrome patients into mice decreases the vasoconstrictor response to serotonin by increasing the release of reactive oxygen species and nitric oxide involving cyclo-oxygenase metabolite, and monocyte MCP-1, via Fas/Fas-ligand pathway [158]. This in vivo study is supported by in vitro studies; EVs derived from inflamed vascular endothelial cells, taken up by recipient cells, such as monocytes (THP-1) and HUVECs, initiate inflammation and promote the adhesion and migration of THP-1 to endothelial cells [117]. Moreover, high glucose concentration, oxidative low density lipoprotein (ox-LDL), and homocysteine produce exosomes derived from monocytes and from endothelial cells that trigger monocyte adhesion to endothelial cells [159,160].
It should be noted that EVs have counter regulatory effects on inflammation, which is cell origin-dependent [161–165]. For example, EVs released from inflamed endothelial cells contain a variety of inflammatory markers, chemokines, and cytokines. Those chemokines and cytokines in those EVs enable the interaction between endothelial cells and monocytes which can lead to either a pro- or anti-inflammatory phenotype [117]. Mature dendritic cell-derived exosomes evoke endothelial inflammation and atherosclerosis by a membrane TNF-α-mediated NF-κB axis, similar to that caused by lipopolysaccharides [162]. By contrast, EVs from thrombin-activated platelets, mononuclear cells, and neutrophils suppress vascular inflammation by producing anti-inflammatory mediators [163–165]. However, even the same EVs from the same tissue or cell may have opposite effects on vascular inflammation. For example, EVs from HUVECs treated with ox-LDL can activate monocytes by shifting the monocyte/macrophage balance from anti-inflammatory M2 macrophages toward proinfammatory M1 macrophages. However, EVs from HUVECs treated with the KLF2, an atheroprotective factor, suppress monocyte activation by enhancing immunomodulatory responses and diminishing proinflammatory responses [166]. These suggest that the EV function depends on the environment surrounding the EV-releasing cells.
3.1.2.3. EVs, coagulation, and thrombosis
Several studies have shown that EVs play important roles in the progression of coagulation and thrombosis [167,168]. Circulating EVs from some thrombosis-susceptible conditions, such as acute coronary syndromes and cancers are increased [169,170]. Microparticles of endothelial origin are elevated in patients with acute coronary syndromes, and contribute to the generation and perpetuation of intracoronary thrombi [169]. High levels of microparticles are present in extracts from atherosclerotic plaques. These microparticles, which are mainly of monocytic and lymphocytic origin, retain most of their total tissue factor activity, including procoagulant potential [142]. One study showed that the procoagulant activity of platelet microparticles in circulating blood is 50- to 100-fold higher than that of activated platelets [171].
Circulating and platelet-derived microparticles promote platelet and fibrin deposition and therefore, thrombosis on the atherosclerotic arterial wall [172]. Microparticles can be procoagulant effectors due to the expression of phospholipids, such as phosphatidylserine, on their surfaces. Negatively charged phosphatidylserine expressed on the surface of platelet microparticles provides a catalytic surface for factor X and prothrombin activation, which are essential in the coagulation process [49,173]. Other molecules and receptors, such as tissue factor and P-selectin glycoprotein ligand-1 (PSGL-1) on the surface of platelet microparticles also increase thrombosis and clot formation. Tissue factor-bearing microparticles, derived from monocytes are recruited in the developing thrombus, by the interaction of PSGL-1 on microparticles with platelet P-selectin [174]. The addition of platelet EVs to vesicle-free human plasma induces thrombin generation in a concentration-dependent manner. This process is inhibited by annexin V, but not by anti-tissue factor antibodies. Thus, the propagation of coagulation is primarily due to the exposure of platelet EVs to phosphatidylserine [175]. However, some EVs, including platelet-derived exosomes and erythrocyte-derived microparticle, can inhibit the progression and development of coagulation and thrombosis [176,177]. In addition, both intrinsic factors such as IL-33 and angiotensin II (Ang II) [178,179], or extrinsic factors, such as particulate matter and cigarette smoke, can modulate the production and release of EVs, and their ability to regulate coagulation and thrombosis [180–182].
3.2. EVs and myocardial infarction
Myocardial infarction evolves from the rupture of unstable atherosclerotic plaques, to coronary thrombosis, and subsequently myocardial ischemia-reperfusion injury. Despite decades of therapeutic advances, acute myocardial infarction remains the principal cause of global cardiovascular morbidity and mortality. It is now accepted that the number of circulating EVs, including endothelial-, platelet-, erythrocyte- and monocytes-derived EVs increases when myocardial infarction occurs, which suggests that EVs may play an important role in the pathogenesis and extent of injury of myocardial infarction.
3.2.1. Increase in EVs after myocardial infarction
Cardiac and circulating EVs are increased in the patients with myocardial infarction. Cardiac EVs in fragments of the interventricular septum, obtained from patients undergoing extracorporeal circulation for aortic valve replacement, have similar diameters of exosomes and microvesicles (microparticles) from infarcted hearts in mice caused by coronary artery ligation. These extracellular vesicles, taken up by infiltrating monocytes, may be responsible for the local inflammation with myocardial infarction [183]. The microvesicles after acute myocardial infarction are generated not only by platelets, but also by monocytes, endothelial cells, and erythrocytes [184,185]. For example, the levels of platelet-derived microvesicles are higher in patients with acute myocardial infarction than healthy controls [186]. In patients with ST-segment elevation myocardial infarction (STEMI), the levels of leukocyte- and endothelial-derived microvesicles, and tissue factor-bearing microvesicles are higher within the occluded coronary artery than in peripheral blood [187]. The levels of microvesicles are also increased in patients with non-ST-elevated myocardial infarction (NSTEMI) [188]. In addition, the contents of plasma microvesicles from STEMI patients are also altered. A proteomic analysis of plasma microvesicles from STEMI patients identified 117 proteins that were different between STEMI and stable coronary artery disease groups. Most of the proteins are involved in inflammation and CVD, with 11 open-reading frames related to infarction [189]. Based on the association between circulating EVs and ischemic heart, plasma EVs and their contained functional molecules, such as miRNAs and certain proteins, may be novel diagnostic biomarkers that can be developed for clinical use to benefit patients with myocardial infarction [190–192]. However, further research is needed to prove this hypothesis.
3.2.2. Effects of released EVs following myocardial infarction
The increase in EVs after myocardial infarction promotes inflammatory responses. Acute myocardial infarction increases the generation of cardiac EVs, exosomes and microvesicles (microparticles), originating mainly from cardiomyocytes and endothelial cells, 15 and 24 h after coronary artery ligation, and returning to basal levels at 48 and 72 h [183]. EVs accumulating in the ischemic myocardium are rapidly taken up by infiltrating monocytes and regulate local inflammatory responses. The cardiac microvesicles not exosomes, generated after myocardial infarction, increase the release of IL-6, CCL2, and CCL7 from cardiac monocytes [183]. Circulating microparticles also promote inflammatory responses after myocardial infarction. These circulating microparticles bind to the inflammatory marker, CRP, which is increased in myocardial infarction [193]. Other studies found that following myocardial infarction, circulating microparticles can convert pentameric CRP (pCRP) to pro-inflammatory monomer CRP (mCRP), and bind to the endothelial cell surface. These results suggest an important role of microparticles in the increased inflammatory response after acute myocardial infarction by transporting and delivering pro-inflammatory mCRP [194]. EVs are also associated with the increase in inflammatory factors in myocardial infarction. For example, vascular cell adhesion molecule-1 (VCAM-1) density is increased in endothelial cell-derived microvesicles in patients with myocardial infarction. The increased VCAM-1 expression in endothelial cell-derived microvesicles at the site of coronary plaques positively correlated with the extent of vascular inflammation and size of the myocardial infarct [195].
EVs released following myocardial infarction have other effects, such as promoting splenic monocyte mobilization and modulating endothelial function. Following acute myocardial infarction, monocytes are mobilized in large numbers from the spleen, activated, and recruited to the damaged myocardium, that may associate with EVs released with myocardial infarction. In patients with STEMI, endothelium-derived extracellular vesicles promote splenic monocyte mobilization and transcriptional activation. These may be the mechanisms by which the ischemic myocardium signals both monocyte mobilization and transcriptional activation, following acute myocardial infarction [196]. The EVs following myocardial infarction can impair the endothelial NO transduction pathway, contributing to the general vasomotor dysfunction, even in angiographically normal arteries [197].
3.3. EVs and hypertension
Hypertension is one of the most common health problems worldwide [198]. The pathogenesis of essential hypertension is complex. Many organs and systems including kidneys, arteries, microcirculation, heart, and the endocrine, gastro-intestinal, immune, and nervous systems are involved in the pathophysiology of hypertension. Among them, arteries and kidneys are major contributors to the development of hypertension [199]. There are emerging pieces of evidence that EVs exert their physiological and pathophysiological functions by modulating arteries and kidneys.
3.3.1. EVs in hypertension
Hypertensive subjects, relative to normotensive subjects, have increased circulating EVs [200]. Moreover, there is a positive relationship between EVs and blood pressure, in that the quantity of endothelial and platelet microvesicles is greatest in the severely hypertensive patients [200,201]. In addition, EVs are associated with hypertensive complications. In hypertensive patients with well-controlled blood pressures, circulating endothelial microvesicles are increased, which positively correlate with brachial-ankle pulse wave velocity (baPWV), a parameter of vascular stiffness [202].
In an animal model of hypertension, the spontaneously hypertensive rat (SHR), circulating levels of endothelial microvesicles are positively associated with endothelial dysfunction and arterial stiffness [203]. Interestingly, SHR-derived plasma exosomes increase systolic blood pressure in normotensive Wistar-Kyoto (WKY) rats. By contrast, WKY-derived exosomes decrease blood pressure in SHRs [204]. Moreover, SHR-derived exosomes, injected intraperitoneally in WKY rats, induce thoracic aortic wall thickening and decrease collagen abundance. By contrast, WKY-derived exosomes tend to reverse those changes observed in SHRs [204]. The blood pressure and structural changes in the aorta in WKY rats and SHRs may be caused by different miRNAs in their exosomes. Twenty-seven miRNAs are differentially expressed between SHRs and WKY exosomes. The top 10 differentially expressed miRNAs are related to some hypertension-specific target genes/signaling pathways, including the TGF-β signaling pathway, MAPK signaling pathway, and insulin signaling pathway [205].
3.3.2. Mechanisms of EV-mediated regulation of blood pressure
3.3.2.1. EVs and vascular dysfunction
Endothelium-mediated vasorelaxation plays an important role in the regulation of blood pressure. Studies have shown that EVs are involved in the progression of impaired endothelial function. Circulating endothelium-derived EVs impair endothelium-mediated vasorelaxation, by decreasing nitric oxide, and increasing superoxide production [206]. The incubation of mouse aortic rings with T lymphocyte-derived EVs impairs vasorelaxation and shear stress-induced dilatation of mesenteric arteries. These effects, apparently, are caused by a decrease in the expression of endothelial nitric oxide synthase and prostacyclin [207]. The impaired endothelial-dependent relaxation induced by EVs may also be caused by EV-contained signaling molecules, such as extracellular signal-regulated kinase (ERK) and cross-talk between endoplasmic reticulum and mitochondria [208,209]. A positive feedback is involved because vascular tension increases the release of the contents of EVs.
Exosomes isolated from thoracic aortic fibroblasts contain increased levels of miR-133a. Although biaxial cyclic stretch increases the plasma levels of exosomes, it reduces miR-133a abundance in thoracic aortic tissue, which is associated with thoracic aortic dilation. This tension-sensitive mechanism reduces miR-133a in aortic fibroblasts through the packaging and secretion of exosomes [210]. Another study showed that cyclic stretch increases the release of EVs from VSMCs, which transfer miR-27a from VSMCs to endothelial cells. Subsequently, miR-27a decreases G-protein-coupled receptor kinase 6 (GRK6) expression, resulting in endothelial cell proliferation that eventually causing vessel obstruction [211]. Other studies also found that another miR, miR-142-3p, from EVs of activated platelets of hypertensive rats, can also promote endothelial cell proliferation [212]. Moreover, exosomes from serum of rats with Ang II-induced hypertension upregulate the expression levels of ICAM-1 and plasminogen activator inhibitor-1 in human coronary artery endothelial cells, suggesting that inflammation of endothelial cells in hypertension may be caused, at least in part, by macrophage-derived exosomes [213]. Thus, the ability of EVs to regulate endothelial inflammation synergizes with the effects of miR-27a and miR-142-3p to increase endothelial cell proliferation and blood pressure.
3.3.2.2. EVs and kidney
Several studies have focused on the effect of urinary EVs and their contents on sodium exchangers, channels, and transporters. Urinary EVs have been reported to contain sodium-potassium-chloride cotransporter 2 (NKCC2), sodium chloride cotransporter (NCC), and epithelial sodium channel (ENaC) [214]. More importantly, these sodium channels and transporters in EVs are altered under hypertensive conditions. For example, the levels of urinary peritubular capillary-endothelial microvesicles (PTC-EMVs) are elevated in both renovascular and essential hypertension, relative to healthy volunteers. Moreover, urinary PTC-EMV levels correlate positively with blood pressure but inversely with estimated glomerular filtration rate. Therefore, urinary PTC-EMVs may be indicative of injury of the renal microcirculation [215].
Urinary NCC protein is about four times higher in patients with familial hyperkalemia and hypertension than in controls. This finding reflects the increased NCC abundance in the apical membrane of distal tubule cells in patients with this disease [216]. The NCC expression and NCC phosphorylation are also higher in urinary exosomes from male kidney transplant recipient patients with hypertension than normotensive patients [217]. In other hypertensive states, such as pre-eclampsia, a hypertensive disorder of pregnancy characterized by hypertension and sodium retention, urinary EVs have increased expression of the ENaCα subunit and phosphorylation of the activating S130 and T101/105 sites in NKCC2, but decreased phosphorylation of the activating T60 site in NCC [218]. However, in another report, the levels of NKCC2 and NCC in urinary exosomes were similar in hypertensive patients and controls [219].
Aquaporins (AQP) are found in urinary EVs. For example, AQP2 in human urine is predominantly localized in exosomes with preserved water channel activities. Saline infusion increases urinary AQP2 in EVs in patients with essential hypertension, suggesting that AQP2 in urinary EVs could detect water balance disorders in hypertension [220,221]. Interestingly, Gildea et al. showed exosomal transfer from human renal proximal tubule cells to distal tubule and collecting duct cells. Stimulation of the human renal proximal tubule cells with fenoldopam, a dopamine D1 receptor agonist, increases exosome production from renal proximal tubule cells. The transfer of these exosomes to distal convoluted tubule cells and collecting duct cells reduces the basal reactive oxygen species production in the recipient cells, presumably by cell-cell interaction. This proximal-to-distal vesicular inter-nephron transfer represents an unrecognized trans-renal communication system [222].
3.3.2.3. EVs and RAS
It is well known that the renin-angiotensin system (RAS) plays a vital role in the development and maintenance of hypertension [223]. Many components of the RAS can be transferred by EVs, which affect the expression and activity of the components of the RAS in the recipient cells. For example, angiotensin-converting enzyme (ACE) contents and activity are much higher in adventitial fibroblast exosomes from SHRs than those from WKY rats. Exosomes from vascular adventitial fibroblasts of SHRs can promote the migration of VSMCs of WKY rats by increasing ACE activity and ACE and Ang II levels [224]. Another study found that exogenously administered angiotensin type 1 receptor (AT1R)-enriched exosomes target cardiomyocytes, skeletal myocytes, and mesenteric resistance vessels and increase the blood pressure response to Ang II in AT1R knockout mice [225]. Our recent study found that EVs from THP-1 cells increase the blood pressure of Sprague-Dawley rats by impairing Ang-(1–7)-mediated vasodilation in mesenteric arteries, which is exaggerated by EVs from lipopolysaccharide-treated THP-1 cells. These are accompanied by a decrease in Mas receptor expression and eNOS phosphorylation in the endothelium of mesenteric arteries of EV-treated Sprague–Dawley rats [226]. We also found that AT1R DNA in the EVs from human plasma homologously or heterologously transferred from donor cells to recipient cells can increase AT1R-coding mRNA, protein expression, and function [100,227]. These studies indicate that RAS components can be transferred by EVs, leading to altered RAS contents in the recipient cells of kidneys and arteries.
In contrast to the ability of EVs to regulate the RAS, EV and its contents can be regulated also by the RAS. The incubation of mouse aortic endothelial cells with Ang II promotes microvesicle formation that involves the NADPH oxidase and Rho kinase pathway. These result in a feed-forward system whereby the damaged endothelial cells create further damage by causing oxidative stress and inflammation [228]. Another study showed that the activation of endogenous RAS by low salt diet or aldosterone administration increases urinary exosomal excretion with an increase in sodium channel expression. Thus, urine exosomal γENaC concentration increased nearly 20-fold, which positively correlated with plasma aldosterone concentration and urinary Na/K ratio [229]. This effect may be specific to γENaC because urine exosomal NCC and αENaC concentrations were relatively unchanged. Moreover, urinary exosome abundance was also not changed because the abundance of the major exosome markers such as multivesicular body marker TSG101 and several tetraspanin proteins (e.g., CD9, CD63, CD81, and CD82), along with proteins consistent with exosome biosynthesis, was not changed [229].
3.4. EVs and heart failure
Heart failure is the result of cardiac remodeling due to stress caused by adverse conditions, such as coronary heart disease, atrial fibrillation, elevated blood pressure, and valvular heart disease [230]. EVs may play a role in the development and progression of heart failure [231].
3.4.1. Altered EVs after heart failure
The levels of circulating EVs increase with the occurrence of heart failure. Heart failure patients have higher levels of serum exosomes or endothelial microvesicles than healthy individuals [232,233]. Moreover, the increased number of circulating endothelial apoptotic microparticles in heart failure patients is associated with poor clinical outcomes, such as increased 3-year chronic heart failure-related death, all-cause mortality, and risk of recurrent hospitalization due to chronic heart failure [234]. Circulating microparticles with apoptotic or non-apoptotic phenotypes, CD144+/CD31+/annexin V+ endothelial apoptotic microparticles and CD31+/annexin V+ endothelial apoptotic microparticles, are useful for risk assessment of 3-year cumulative fatal and non-fatal cardiovascular events in chronic heart failure patients [235]. The levels CD31+/annexin V+ circulating microparticles are increased while the levels of CD62E+ circulating microparticles are decreased in heart failure patients with metabolic syndrome; decreased CD62E+ to CD31+/annexin V+ ratio may be a surrogate marker of chronic heart failure in metabolic syndrome [236]. Increased circulating EV levels are associated with specific phenotypes of chronic heart failure, such as heart failure with predominantly reduced left ventricular ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF) and heart failure with mid-range ejection fraction (HFmrEF) [237]. The number of circulating CD144+/annexin V+ microvesicles in HFrEF patients is significantly higher than in HFmrEF and HFpEF patients. The combination of the number of circulating CD31+/annexin V+ microvesicles and galectin-3 (Gal-3) may be the best predictor of HFpEF and that the number of circulating CD144+/annexin V+ microvesicles increases the predictive capabilities of soluble growth stimulation expressed gene 2 (sST2) (sST2) and Gal-3 for HFrEF [237].
3.4.2. Adverse effects of EVs in heart failure
Increased circulating EVs exert their adverse effects in heart failure, in part, by promoting coagulation. Procoagulant endothelial cell-derived EVs are elevated in acute decompensated heart failure, causing an increase in plasma thrombin generation and thus, a hypercoagulable state [238]. Another study showed that the levels of phosphatidylserine+ microparticles and phosphatidylserine+ blood cells are increased in patients with heart failure, compared with healthy controls [239]. These circulating phosphatidylserine+ microparticles interacted with phosphatidylserine+ blood cells to shorten the coagulation time and increase FXa/thrombin generation and fibrin formation in the heart failure group. Therefore, phosphatidylserine on the injured blood cells and microparticles plays a pivotal role in the hypercoagulable state in heart failure patients [239].
Increased circulating EVs are also associated with increased inflammatory response and enhanced oxidative stress in chronic heart failure [240–242]. Plasma-derived exosomes carrying mtDNA trigger an inflammatory response via the TLR9-NF-κB pathway in chronic heart failure patients. The inflammatory response is closely related to exosomal mtDNA copy number [101]. Another study showed that inflammation-associated microRNAs are altered in circulating exosomes of heart failure patients, e.g., elevated circulating exosomal but not plasma miR-146a/miR-16. miR-146a is induced in response to inflammation, as a part of anti-inflammatory response [241]. The oxidative stress in chronic heart failure occurs because of an imbalance between the synthesis and degradation of reactive oxygen species. MicroRNA-enriched exosomes contribute to the dysregulation of oxidative stress in chronic heart failure. In chronic heart failure, exosomal microRNA-27a, microRNA-28-3p, and microRNA-34a, are increased which contribute to the oxidative stress by inhibition of the translation of nuclear factor erythroid 2-related factor 2 (Nrf-2) [242].
3.5. EVs and atrial fibrillation
Cardiac arrhythmias are common and contribute substantially to cardiovascular morbidity and mortality [243]. Atrial fibrillation is one of severe cardiac dysrhythmias in patients with CVD. Atrial fibrillation increases the risk of stroke and heart failure and is also associated with various disease conditions, such as hypertension and coronary artery disease [244]. However, the underlying pathophysiology of atrial fibrillation is complex and remains incompletely understood.
Circulating EVs are increased in all types of atrial fibrillation, except for long-standing persistent atrial fibrillation, which has not been studied [245–255]. The levels of circulating platelet microvesicles are higher in valvular atrial fibrillation patients than controls [246]. In patients with nonvalvular persistent but not paroxysmal atrial fibrillation, total circulating microvesicles levels are also increased [245]. However, in another study of patients with nonvalvular atrial fibrillation, both the platelet- and endothelial cell (CD31+ CD41−)-derived microvesicles are elevated, regardless of the type of nonvalvular atrial fibrillation. By contrast, CD144+ endothelial microvesicles and phosphatidylserine expressing microparticles are not different between patients with nonvalvular atrial fibrillation and healthy controls [247]. The increase in circulating procoagulant microvesicles may reflect a hypercoagulable state and contribute to atrial thrombosis and thromboembolism. The increase in circulating procoagulant microvesicles is also seen in patients with CVD without nonvalvular atrial fibrillation [248,249]. Acute episodes of atrial fibrillation are associated with a decrease in microvesicle-associated tissue factor activity, possibly related to their consumption, which in turn favors coagulation and the local production of thrombin [250]. Choudhury et al. reported that there is no difference in levels of platelet microvesicles between patients with paroxysmal and permanent atrial fibrillation, although atrial fibrillation patients have higher levels of platelet microvesicles compared with healthy control subjects [251]. Nevertheless, the increase in circulating procoagulant microvesicles (endothelial and platelet microvesicles) in nonvalvular atrial fibrillation is independent of CVD [248]. It should also be noted that there are no atrial-specific differences in the levels of total procoagulant microvesicles, leukocyte- or platelet-derived microvesicles, although thrombi form mainly in the left rather than the right atria of patients with atrial fibrillation [252]. Endothelial cell-derived microvesicles and tissue factor activity and collagen-induced platelet aggregation are slightly elevated in the right atrium, which challenges the current dictum for increased thrombogenic status in the left atrium, that could account for the greater propensity for thrombus formation in patients with atrial fibrillation [252].
The contents of circulating EVs are also altered in patients with atrial fibrillation. Tissue factor, annexin V, IL-1β, and P-selectin are increased in microvesicles/EVs of patients with nonvalvular atrial fibrillation [245,247,248]. This is similar to another study, showing that acute-onset atrial fibrillation increases the expression of P-selectin in platelets and microvesicles, and activates platelets within minutes to initiate platelet-mononuclear cells interaction, which subsequently induces tissue factor expression in patients with chronic atrial fibrillation [253]. However, some contents of microvesicles or EVs, such as mtDNA, are not altered in the patients with atrial fibrillation [254].
MicroRNA and DNA are also changed by atrial fibrillation. Forty-five microRNAs in exosomes are increased in patients with persistent atrial fibrillation, but not in patients with paroxysmal atrial fibrillation, relative to the levels in patients with supraventricular tachycardia control. Indeed, the expression of five miRNAs (miRNA-103a, −107, −320d, −486, and let-7b) are elevated by more than 4.5-fold in patients with persistent atrial fibrillation, which are involved in atrial function and structure, oxidative stress, and fibrosis [255]. Another study found that plasma exosomal miR-483-5p in increased, but miR-142-5p, miR-223-3p and miR-223-5p are decreased in patients with nonvalvular persistent atrial fibrillation [256].
3.6. EVs and other cardiovascular diseases
In addition to the above diseases, EVs are also associated with other CVDs, including aortic aneurysm, dilated cardiomyopathy, congenital heart disease, mitral valve disease, and Kawasaki disease.
Aortic aneurysm is an abnormal dilatation of the aorta, caused by the degeneration of the extracellular matrix of the blood vessel wall [257]. Plasma microvesicles are elevated in patients with large aneurysms (>45 mm) of the ascending aorta [258]. There is a positive correlation between aneurysm diameter and plasmin activity, as well as microvesicles release [259]. Patients with abdominal aortic aneurysm have increased microparticles in plasma and eluates from the luminal thrombus layer, relative to other layers [260]. The microparticles are probably the major procoagulants in abdominal aortic aneurysms because their removal from the luminal layer eluates prolongs the clotting time [260]. EVs can also aggravate the formation of aortic aneurysm via multiple mechanisms. For example, the amount officolin-3 in microvesicles is associated with the progression of abdominal aortic aneurysm [261]. Increasing mechanical stretch induces microparticle formation from vascular smooth muscle and endothelial cells leading to ER stress/inflammation-dependent endothelial dysfunction during the development of thoracic aortic aneurysm and subsequent dissection [262]. Proteomic analysis showed that there are different protein profiles in human plasma-derived microvesicles between abdominal aortic aneurysms and control subjects. Some of those proteins are involved in oxidative stress, immune-inflammation, and thrombosis, which can accelerate the progression of the aneurysm [263].
Congenital heart disease is the most common congenital malformation [264]. Patients with cyanotic congenital heart disease with polycythemia have more circulating platelet microparticles than patients with acyanotic congenital heart disease; the production of circulating platelets markedly increases with >60% hematocrit [265,266]. Nevertheless, platelet-derived microparticles are also increased in children with acyanotic congenital heart disease. These platelet-derived microparticles may be involved in pathogenesis of coagulation/hemostatic abnormalities, especially in children with cyanotic heart disease [266]. Similar to the increase in platelet microvesicles in children with cyanotic and acyanotic congenital heart disease, adults with acyanotic congenital heart disease have increased endothelial-derived microparticles that could contribute to increased inflammation, via P38 MAPK/TNFα/interleukin-6 pathway [267]. Interestingly, Shi R et al. found that maternal exosomes in diabetes cross the maternal-fetal barrier and contribute to the genesis of congenital heart disease, possibly via miRNAs, such as miR-133, miR-30, miR-99, and miR-23 that are involved in cardiac development. Therefore, abnormalities in maternal exosomes may contribute to the impairment of cardiac development in the offspring [268].
Patients with mitral valve disease have increased plasma endothelial microparticles. These microparticles impair human mitral valve endothelial cell function via the inhibition of the Akt/eNOS-HSP90 signaling pathway [269]. In Kawasaki disease patients with coronary artery aneurysms, a proteomics study identified 32 differentially expressed proteins from serum exosomes, which are associated with multiple functions, including host immune response, inflammation, apoptosis, development, and adhesion [270]. Specifically, tetranectin, a plasma protein secreted by monocytes, neutrophils, and macrophages and retinol binding protein 4, that may be protective against cardiovascular events, are decreased in patients with Kawasaki disease with carotid artery aneurysms. By contrast, leucine-rich alpha-2-glycoprotein, which may be involved in cell adhesion and apolipo-protein A-IV, are increased in patients with Kawasaki disease with carotid artery aneurysms [271]. These findings establish a comprehensive proteomic profile of serum exosomes from children with coronary artery aneurysms caused by Kawasaki disease, and may provide additional insights into the mechanisms of coronary artery aneurysms caused by Kawasaki disease.
4. Diagnostic and therapeutic potential of EVs in CVDs
4.1. Diagnostic potential of EVs in CVDs
4.1.1. Levels of EVs in diagnostic or prognostic potential of CVDs
Numbers of studies have shown that EVs derived from different origins such as platelets, erythrocytes, leukocyte, and endothelial cells may be considered as valuable markers for the diagnosis or prognosis of CVDs [185,234,272]. Until now, most of the studies showed increased EV levels in the circulating of patients with CVDs. For example, microparticles from red blood cells have been shown to be increased in STEMI; moreover, erythrocyte microparticles are related to the output of creatine kinase-myocardial brain fraction, a myocardial damage biomarker [185]. Compared to patients without the atherosclerosis, stroke patients with carotid atherosclerosis exhibits increased concentration of CD62P+/CD61+ and PAC-1+/CD61+ microvesicles, indicating platelet-derived microvesicles may have a predictive value for the next vascular event in patients with a history of stroke [272]. In another study, Berezin et al. found that higher number of circulating endothelial-derived apoptotic microparticles is associated with increased 3-year chronic heart failure-related death, all-cause mortality, and risk of recurrent hospitalization in the patients with ischemic symptomatic chronic heart failure [234].
Furthermore, the circulating levels of EVs are associated with the CVD risk stratification. For example, Sarlon-Bartoli et al. showed that compared to patients with stable plaque, the plasma level of leukocyte-derived microparticles are elevated in patients with unstable plaque, indicates that leukocyte-derived microparticles may be a potential biomarker associated with plaque vulnerability in patients with high-grade carotid stenosis [146]. Del Turco et al. found that the procoagulant activity of circulating microparticles is higher in patients with moderate calcified atherosclerotic plaque than non-calcified plaque patients, indicating that it may be a biomarker to indicate a state of blood vulnerability that may locally precipitate plaque instability and increase the risk of subsequent major cardiovascular events. Another study showed that endothelial cells-derived microparticles are elevated in the unstable than the stable plaque patients, suggesting its role in predicting plaque instability in carotid patients [273]. It should be noted that the above-mentioned changes of EV levels in CVDs are only correlation study, whether or not those changes could be taken as clinic biomarkers to indicate that diagnostic or prognostic potential of CVDs needs to be deeply investigated in the further.
4.1.2. Contents of EVs in diagnostic or prognostic potential of CVDs
EVs contents, especially miRNAs, have been shown as potential biomarkers for the diagnosis or prognosis of CVDs. Jansen et al. found that decreased expression of miR-126 and miR-199a in circulating microvesicles, but not freely circulating miRNA expression, is associated with a higher major adverse cardiovascular event rate, suggesting its role to predict the occurrence of cardiovascular events in patients with stable coronary artery disease [274]. Moreover, exposure to some risk factors such as hyper-cholesterolemia and atherogenic lipoproteins modifies the miRNA profile of VSMCs-derived microvesicles, which are reflected in patients with familial hypercholesterolemia [275,276]. de Gonzalo-Calvo et al. showed that, compared with normo-cholesterolemic controls, miR-24-3p and miR-130a-3p in circulating microvesicles are decreased in familial hyper-cholesterolemia patients; however, only plasma levels of miR-130a-3p are inversely associated with coronary atherosclerosis [275]. Another study found that compared to non-atherosclerotic areas, levels of miR-143-3p and miR-222-3p are lower in the microparticles derived from atherosclerotic plaque areas; however, only the concentration of miR-222-3p is decreased in circulating microparticles from familial hypercholesterolemia patients compared to normo-cholesterolemic controls [276]. These suggest that the cargo of EVs may be a potential biomarker for coronary atherosclerosis [277].
Another important EVs content, protein, has also been suggested as a potential biomarker of CVDs. de Hoog et al. identified the concentrations of some proteins including polygenic immunoglobulin receptor, cystatin C, and C5a from serum EVs are independently associated with acute coronary syndrome [278]. A clinical long-term follow-up studies by Sinning et al. found that the increased circulating CD31+/Annexin V+ microparticles is an independent predictor of cardiovascular events in patients with stable coronary artery disease, indicating that it may be useful for risk stratification [279]. Circulating microparticles with CD3+/CD45+ and SMAα+ are higher in older subjects with moderate-to-high CVD risk, who will develop a major cardiovascular event [280]. In addition, other EVs contents such as DNAs may be also associated with the diagnosis of CVDs. Cai et al. showed that plasma EVs from male patients with coronary artery disease have increased SRY (sex-determining region, Y) gene copy number than healthy subjects. Moreover, SRY gene transferred by EVs accelerates atherosclerosis by promotion of leucocyte adherence to endothelial cells, indicating that DNAs in plasma EVs may potential biomarkers of atherosclerosis [281]. However, similar with the plasma EV changes as possible biomarker, it should be noted that the role of above altering cargos in EVs contribute to the diagnosis of CVDs remains to be future investigated.
4.2. Therapeutic potential of EVs in CVDs
4.2.1. Therapeutic potential of EVs
The regulatory effects of EVs in cardiovascular physiology and pathology have engendered interest in the therapeutic potential of EVs. The therapeutic effects of stem cells, especially MSC-derived EVs, are of interest. Several studies have shown that exosomes derived from various sources promote angiogenesis after myocardial infarction via multiple mechanisms [282,283]. MicroRNAs such as miR-132 and miR-125a from human adipose tissue- and bone marrow-derived MSC-exosomes delivered to endothelial cells enhance the neovascularization in the peri-infarct zone and preserve myocardial function [282,283]. Comprehensive proteomic analysis of HUVECs cultured with peripheral arterial disease-derived MSC exosomes found that the NF-κB signaling pathway is the key mediator of MSC exosome-induced angiogenesis in endothelial cells [284]. MSC-derived exosomes ameliorate cardiac damage from myocardial ischemia/infarction by activating the S1P/SK1/S1PR1 signaling, promoting macrophage M2 polarization, but inhibiting myocardial cell apoptosis via the PI3K/Akt/mTOR pathway [285–287]. The MSC-derived exosomes can also provide myocardial protection from ischemia/reperfusion injury by inducing cardiomyocyte autophagy, via the AMPK and Akt pathways [134,288]. Cardiomyocyte autophagy meta-analysis showed that MSC-derived EVs reduce infarct size and ameliorate cardiac function, involving the Wnt/β-catenin, ERK1/2, and PI3K/Akt pathways in animals with myocardial infarction [287].
MSC-derived EVs also exert their therapeutic effect in blood vessels [289,290]. For example, MSC-derived exosomes attenuate the progression of atherosclerosis in ApoE−/− mice, via miR-let7-mediated infiltration and polarization of M2 macrophages [291]. Adipose tissue MSC-derived EVs prevent vein graft neointima formation by inhibiting VSMC proliferation and migration, reducing macrophage migration, and decreasing inflammatory cytokine expression [292]. MSC-derived exosomes from human are well tolerated in animal models, without adverse effects on liver and renal function or allergic response. MSC-derived exosomes do not have adverse effects on red blood cells, skeletal muscles, arteries, and veins [293].
4.2.2. Delivery of EVs in vivo
The delivery system has to be taken into consideration for EVs to exert their therapeutic effects. EVs, unlike cells, are able to maintain their integrity even after many freezing and thawing cycles [294,295]. The presence of a resistant membrane for EVs makes it possible for long-term storage without biological degradation [296]. The lipid bilayer membrane structure of EVs can protect their encapsulated content against degradation and resist RNase damage to nucleic acids [297]. Their small size allows them to circulate all over the body, rapid clearance from the circulation, and their passive entrance in tissues to perform their functions [298]. Importantly, EVs are biocompatible, and can be immunologically inert to evade the host immune system [299].
There are several drug delivery systems of EVs [300,301], which can be classified into two methods. The first method is the simple incubation of EVs with the cargo. Thus, the incorporation of an anti-inflammatory drug curcumin into exosomes increases not only their solubility, stability, and bioavailability of curcumin, but also enhances their anti-inflammatory activity without toxic effects [302]. The second method is to improve the effectiveness of EVs to encapsulate cargo, including the use of commercial transfection reagents, adeno-associated viruses (AAVs) encapsulated in EVs, sonication, and electroporation [14]. For example, the electroporation of MSC-derived exosomes with miR-132 mimics increases tube formation of endothelial cells and promotes angiogenesis in myocardial infarction [282]. EVs loaded with human epithelial growth factor receptor-2 (HER2) siRNA by sonication are taken up by recipient cells and lead to the reduction of HER2 protein expression and inhibition of breast cancer development and progression [303]. AAVs are very effective for in vivo gene manipulation. AAVs that are encapsulated in EVs become more effective than free AAVs in the delivery of genes into recipient cells [304,305]. EVs containing AAVs also enable anti-AAV antibody evasion [306]. The above methods of drug delivery via EVs may increase the efficacy of drugs or other EV contents. It should be noted that loading exosomes directly into recipient or donor cells is an alternative method, including incubation, electroporation, and transfection of exosomes or transfection, incubation, and activation of the parent cells.
5. Conclusion and perspective
In summary, many studies have highlighted the contribution of EVs in the regulation of a wide range of normal cellular physiological processes, including waste scavenging, cellular stress reduction, intercellular communication, immune regulation, and cellular homeostasis modulation (Fig. 2). EVs play vital roles in both cardiovascular physiological and pathological processes. Depending upon the cell type of origin, EVs can contribute to the pathophysiological development and progression of CVDs. Altered circulating EVs in plasma of patients with CVDs, their expression pattern, and their contents, especially miRNAs (Table 1), may serve as potential diagnostic and prognostic biomarkers in diverse cardiovascular pathologies. Due to their innate characteristics and physiological functions, EVs, in turn, become potential candidates as therapeutic agents for CVDs. Increased understanding of EVs in the regulation of the cardiovascular system may provide novel concepts in the pathogenesis of CVDs and diagnostic and therapeutic strategies.
Fig. 2.
Schematic representation of biological function of EVs. The cargos of EVs include proteins, lipids, coding RNAs, noncoding RNAs, and DNA fragments. These contents, in EVs, can be transported to neighboring and distant cells and regulate cellular physiological processes, including waste scavenging, cellular stress reduction, intercellular communication, immune regulation, and cellular homeostasis modulation, in the recipient cells.
Table 1.
Summary of EV originated-miRNAs involved in CVDs in this review.
| origination | Types | Expression in CVDs | Effects of EVs originated-miRNAs on CVDs and related functions | References |
|---|---|---|---|---|
| EVs derived from different cells or tissues | ||||
| Exosomes derived from activated macrophages | miR-155 | Increased in macrophages and cardiac fibroblasts of injured hearts | Inhibits fibroblast proliferation and increases fibroblast inflammation after myocardial infarction | [95] |
| Exosomes derived from M1 macrophages | miR-222 | Accelerates VSMCs proliferation and migration, leading to aggravate neointimal hyperplasia | [154] | |
| Exosomes isolated from thoracic aortic fibroblasts | miR-133a | Decreased in thoracic aortic tissue treated with elevated wall tension; increased in the plasma in plasma of hypertensive human subjects and models | Associated with thoracic aortic dilation | [210] |
| Microparticles from VSMCs | miR-27a | Upregulated by pathologically elevated cyclic stretch | Decreases GRK6 expression, leading to endothelial cell proliferation that eventually causing vessel obstruction | [211] |
| Exosomes from cardiac myocytes and fibroblasts | miR-27a, miR-28-3p, miR-34a | Increased in the left ventricle of infarcted hearts | Inhibits the translation of Nrf-2, leading to the increased oxidative stress | [242] |
| Circulating EVs | ||||
| Circulating exosomes derived from patients with paroxysmal AF and persistent AF | miRNA-103, miRNA-107, miRNA-320, miRNA-486, miRNA-let-7b | Increased by more than 4.5-fold in patients with persistent AF | Involved in atrial function and structure, oxidative stress, and fibrosis pathways | [255] |
| Plasma exosomes derived from persistent AF and sinus rhythm patients | miR-483-5p, miR-142-5p, miR-223-3p | Increased levels of miR-483-5p, decreased levels of miR-142-5p, miR-223-3p and miR-223-5p in patients with AF | miR-483-5p, miR-142-5p, miR-223-3p are related with AF | [256] |
| Exosomes in the blood from diabetic pregnant mice | miR-133, miR-30, miR-99, miR-23 | Involved in cardiac development | [268] | |
| Circulating microvesicles from patients with stable CAD | miR-126, miR-199a | Reversely associated with a major adverse cardiovascular event rate | [274] | |
| Circulating microvesicles derived from human coronary artery SMCs in patients with FH and CAD | miR-24-3p. miR-130a-3p | Decreased in FH patients | Inversely associated with coronary atherosclerosis | [275] |
| Microparticles derived from circulating and atherosclerotic plaque areas, and from human coronary artery SMCs | miR-143-3p, miR-222-3p | Decreased levels of miR-222-3p in circulating microparticles from FH patients; decreased levels of miR-143-3p and miR-222-3p in microparticles derived from atherosclerotic plaque areas and human coronary artery SMCs treated with pathophysiological conditions, such as hypercholesterolemia | [276] | |
| Microparticles derived from activated platelets | miR-142-3p | Increased in platelet-derived microparticles in hypertensive rats | Promotes endothelial cell proliferation | [212] |
| MSCs- or ADSCs-derived EVs | ||||
| MSCs-derived exosomes | miR-182 | Regulates macrophage polarization, attenuates MI-reperfusion injury | [93] | |
| MSC-derived EVs | miR-210 | Improves infarcted cardiac function by promotion of angiogenesis | [96] | |
| MSCs-derived exosomes | miR-125b | Inhibits VSMCs proliferation and migration, and suppresses neointimal hyperplasia | [152] | |
| Human bone marrow-derived MSC-exosomes | miR-132 | Enhances the neovascularization in the peri-infarct zone and preserves myocardial function | [282] | |
| Exosomes secreted by human adipose-derived MSCs | miR-125a | Modulates endothelial cell angiogenesis through promoting formation of endothelial tip cells | [283] | |
| ADSCs-derived exosomes | miR-93-5p | Increased following acute MI in patients and animal models | Prevents cardiac injury by inhibiting autophagy and the inflammatory response | [94] |
ADSCs, adipose-derived stromal cells; Af, atrial fibrillation; CAD, coronary artery disease; FH, Familial Hypercholesterolemia; GRK6, G-protein-coupled receptor kinase 6; MI, myocardial ischemia; MSCs, mesenchymal stem cells; Nrf-2, nuclear factor erythroid 2-related factor 2; SMCs, smooth muscle cells; VSMCs, vascular smooth muscle cells.
Acknowledgments
These studies were supported, in part, by grants from the National Natural Science Foundation of China (31730043, 81770425), National Key R&D Program of China (2018YFC1312700), Program of Innovative Research Team by National Natural Science Foundation (81721001), Grant from The Third Affiliated Hospital of Chongqing Medical University (KY19024), and the National Institutes of Health, USA (R01 DK039308, DK119652, and P01 HL074940).
Footnotes
Conflict of interest
The authors declare that they have no competing interests. This manuscript is an original contribution, not previously published, and not under consideration for publication elsewhere.
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