Extracellular Vesicles in Cardiovascular Theranostics

Abstract

Extracellular vesicles (EVs) are small bilayer lipid membrane vesicles that can be released by most cell types and detected in most body fluids. EVs exert key functions for intercellular communication via transferring their bioactive cargos to recipient cells or activating signaling pathways in target cells. Increasing evidence has shown the important regulatory effects of EVs in cardiovascular diseases (CVDs). EVs secreted by cardiomyocytes, endothelial cells, fibroblasts, and stem cells play essential roles in pathophysiological processes such as cardiac hypertrophy, cardiomyocyte survival and apoptosis, cardiac fibrosis, and angiogenesis in relation to CVDs. In this review, we will first outline the current knowledge about the physical characteristics, biological contents, and isolation methods of EVs. We will then focus on the functional roles of cardiovascular EVs and their pathophysiological effects in CVDs, as well as summarize the potential of EVs as therapeutic agents and biomarkers for CVDs. Finally, we will discuss the specific application of EVs as a novel drug delivery system and the utility of EVs in the field of regenerative medicine.

Keywords: Extracellular vesicles; biomarkers.; cardiovascular diseases; exosomes; microvesicles; therapeutic agents.

Figure 1

Extracellular vesicles (EVs) with different contents can be released from cells (A) Early endosome-derived internal multivesicular bodies (MVB) either fuse with lysosomes or fuse with the plasma membrane to release exosomes(40-100 nm diameter); microvesicles (100-1000 nm diameter) are vesicles that bud out in the extracellular space directly from the plasma membrane. (B) Schematic representation of EV cargos, including proteins (e.g., exosome surface proteins such as CD9, CD63, and CD81), lipids, nucleic acids, and non-coding RNAs (e.g., microRNA and lncRNA). ER, endoplasmic reticulum.

Figure 2

Extracellular vesicles (EVs) in the crosstalk of cardiac cells (A) FB-derived exosomes enriched with miR-21-3p or Spp1 and EGFR proteins are transferred to CMs, leading to CM hypertrophy. (B) EVs secreted from CMs or MSCs, as well as circulating EVs exert regulatory effects on CM apoptosis. (C) CM-derived exosomal HSP90 together with secreted IL-6 are able to activate STAT-3 signaling in cardiac FBs, leading to cardiac fibrosis; whereas CM-derived exosomes from exercised diabetic mice express high levels of miR-29b and miR-455, thus reducing cardiac fibrosis. (D) EVs secreted from CMs or MSCs are transferred to ECs, exerting pro- or anti-angiogenic activities. CM, cardiomyocyte; FB, fibroblast; EC, endothelial cell; Spp1, osteopontin 1; EGFR, epidermal growth factor receptor; RAS, renin angiotensin system; HSP, heat shock protein; TLR4, Toll-like receptor 4; SOD1, superoxide dismutase 1; PDGF, platelet-derived growth factor; EGF, epidermal growth factor; FGF, fibroblast growth factor; VEGFR2, vascular endothelial growth factor receptor 2; IGF-1, insulin-like growth factor 1.

Figure 3

Stem cell-derived extracellular vesicles (EVs) and circulating EVs have potential therapeutic effects in cardiovascular diseases (CVDs) EVs derived from different types of stem cells (e.g., MSCs, ESCs, CPCs, and DCs) (A) exert evident beneficial effects in MI, I/R injury, stroke, and pulmonary hypertension, which are mediated via suppression of CM apoptosis, stimulation of angiogenesis, reduction of oxidative stress, and attenuation of fibrosis. Circulating EVs (B) also reduce CM apoptosis and protect against I/R injury. MSC, mesenchymal stem cell; ESC, embryonic stem cell; CPC, cardiac progenitor cell; DC, dendritic cell; CM, cardiomyocyte; MI, myocardial injury; I/R, ischemia/reperfusion.