Circulating Extracellular Vesicles in Cardiovascular Disease

Abstract

Despite notable advancements in clinical care, cardiovascular disease (CVD) remains a leading global cause of mortality. Encompassing a wide range of heart and blood vessel disorders, CVD requires targeted prevention and treatment strategies to mitigate its public health impact. In recent years, extracellular vesicles (EVs) have emerged as crucial mediators of intercellular communication, influencing key processes such as vascular remodeling, inflammation, and immune responses in CVDs. EVs, including exosomes and microvesicles, carry bioactive molecules such as miRNAs, proteins, and lipids that contribute to disease progression. They are released by various cell types, including platelets, erythrocytes, leukocytes, endothelial cells, and cardiomyocytes, each playing distinct roles in cardiovascular homeostasis and pathology. Given their presence in circulating blood and other body fluids, EVs are increasingly recognized as promising non-invasive biomarkers for CVD diagnosis and prognosis. Furthermore, EV-based therapeutic strategies, including engineered EVs for targeted drug delivery, are being explored for treating atherosclerosis, myocardial infarction, heart failure, and hypertension. However, challenges remain regarding the standardization of EV isolation and characterization techniques, which are critical for their clinical implementation. This review highlights the diverse roles of EVs in CVD pathophysiology, their potential as diagnostic and prognostic biomarkers, and emerging therapeutic applications, clearing the way for their integration into cardiovascular precision medicine.

Keywords: atherosclerosis; biomarkers; cardiovascular disease; exosomes; extracellular vesicles; heart failure; hypertension; miRNA; microparticles; myocardial infarction.

Figure 1

Extracellular vesicles (EVs). (A) EVs serve as carriers for bioactive cargo, including enzymes, cytokines, chemokines, miRNAs, and lipids. On the surface, exosomes (EXOs) express the specific tetraspanins CD63, CD9, and CD81, while microvesicles (MVs) present phosphatidylserine (PS) and phosphatidylethanolamine (PE). (B) EXOs are generated by exocytosis: the Endosomal Sorting Complexes Required for Transport (ESCRT), along with auxiliary proteins (Alix, VPS4, VTA-1), recognize ubiquitination-modified proteins and screen specific molecules into exosomal precursors enabling the formation of intraluminal vesicles (ILVs). Then, ESCRT-III complex is required for the formation of spirals, which cause inward budding and vesicle fission to produce multivesicular bodies (MVBs). When MVBs fuse with the plasma membrane, exosomes are discharged into the extracellular environment. In contrast, MVs are formed by ectocytosis, i.e., the outward budding of the plasma membrane. This process is facilitated by a calcium-dependent mechanism that induces cytoskeletal alterations on the plasma membrane. External signals cause an increase in intracellular calcium, which disrupts asymmetry in the double phospholipid layer by influencing the activity of various enzymes such as flippases (inward-directed pumps), floppases (outward-directed pumps), and scramblases (enzymes that promote unspecific bidirectional redistribution across the bilayer). Calcium ions also play a role in the activation of enzymes such as gelsolin and calpain, which disassemble the actin cytoskeleton. This alteration in the actin cytoskeleton influences the curvature and protrusion of the plasma membrane, facilitating the detachment of microvesicles from the membrane.

Figure 2

The multifaceted roles of EVs in cardiovascular remodeling and inflammation. EVs have demonstrated the ability to transport biological content to target endothelial cells, smooth vascular muscle cells, and atherosclerotic plaques, thereby influencing vascular function and the progression of CVDs. The panel on the right lists the main cellular sources of EVs involved in these processes.