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Cardiovascular disease remains the leading cause of death worldwide, creating a continuing need for better ways to detect disease earlier, understand how it progresses, and develop more targeted treatments. Extracellular vesicles, or EVs, are increasingly being investigated as tools that could contribute to each of these goals.
Researchers from the Cardiovascular Research Center at Massachusetts General Hospital examined the growing role of extracellular vesicles in cardiovascular disease.
How extracellular vesicles carry biological information
Extracellular vesicles are tiny membrane-bound particles released by cells. They contain biological molecules such as RNA, proteins, lipids, and metabolites that often reflect the condition of the cells that produced them.
EVs can travel to other cells and deliver their molecular cargo. Once transferred, these molecules can alter gene expression, protein activity, and other cellular processes. This makes extracellular vesicles an important form of communication between cells and tissues.
In cardiovascular disease, EVs released by heart muscle cells, blood vessels, immune cells, and other cell types may provide information about processes such as inflammation, tissue injury, blood vessel formation, and cardiac remodeling.
Communication between the heart and other organs
One important aspect of EV biology is their potential role in communication between organs.
Cardiovascular health is closely connected with the kidneys, liver, brain, and adipose tissue. The researchers discuss how extracellular vesicles may participate in communication along heart-kidney, heart-liver, brain-heart, and adipose-heart pathways.
Because EVs can transport biological signals through the circulation, they may help researchers understand how disease affecting one organ contributes to changes elsewhere in the body.
Functional roles of extracellular vesicle (EV) cargo in cardiovascular disease pathophysiology
EVs carrying microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), damage-associated molecular patterns (DAMPs), and proteins mediate both pathogenic (red arrows) and protective/reparative (green arrows) intercellular signaling across 5 cardiovascular disease contexts. In atherosclerosis and coronary artery disease, EVs enriched in miR-27b-3p, miR-21-5p, miR-146a, miR-223, and Rap1 (Ras-proximate-1) activate NF-κB (nuclear factor-κB), MAPK (mitogen-activated protein kinase), and ICAM (intercellular adhesion molecule)-1)/VCAM-1(vascular cell adhesion molecule-1) programs to weaken the endothelial barrier, drive vascular smooth muscle cell (VSMC) proliferation, and sustain foam cell formation and plaque inflammation. In myocardial infarction and ischemia-reperfusion injury, EV-borne DAMPs, miR-503, miR-155-5p, miR-21, and SPARC (secreted protein acidic and rich in cysteine) engage pattern-recognition receptors, activate the inflammasome and JAK (Janus kinase)/STAT (Signal Transducer and Activator of Transcription) signaling, and drive cardiomyocyte apoptosis, mitochondrial dysfunction, and extensive fibrosis. In myocarditis and cardiomyopathies, EVs carrying viral RNA, miR-142-5p, miR-155, and lnc971 activate PKM2 (pyruvate kinase M2)/HIF-1α metabolic reprogramming, T-cell and macrophage-driven immune activation, and fibroblast fibrosis culminating in contractile dysfunction. In heart failure, EV cargo including miR-21-3b, miR-146a, miR-30d, and TGF-β (transforming growth factor beta) activates PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B) and MAPK to promote hypertrophy and fibrosis, while PPARα (proliferator-activated receptor α) suppression and reduced nitric oxide signaling drive endothelial dysfunction. In cardiac arrhythmias, EV-delivered miR-1-3p, miR-133a-3p, and lncRNAs dysregulate ion channel function and RyR (ryanodine receptor))/SERCA (sarco/endoplasmic reticulum Ca2+-ATPase) calcium homeostasis, increasing electrical heterogeneity and risk of atrial fibrillation and ventricular arrhythmias. Middle depicts the principal EV cargo classes executing these disease-specific signaling programs. Afib indicates atrial fibrillation; cTnT, cardiac troponin T; HFmEF heart failure with mid-range ejection fraction; HFpEF heart failure with preserved ejection fraction; HFrEF heart failure with reduced ejection fraction; miR, microRNA ; RBC, red blood cell; and VT, ventricular tachycardia.
Extracellular vesicles as liquid biopsy biomarkers
EVs also have potential as biomarkers because their molecular cargo can change when cells are injured or diseased. Measuring extracellular vesicles circulating in blood could therefore provide a way to obtain information about cardiovascular tissues without directly sampling them.
Previous research has already demonstrated that plasma EV transcriptomes can differ among forms of acute decompensated heart failure, supporting their potential use in liquid biopsy approaches.
The researchers propose a three-tier framework for evaluating circulating EV biomarkers based on the amount of clinical validation supporting them. They also emphasize the importance of how blood samples are collected, processed, and stored because these steps can influence EV measurements.
Greater standardization will be necessary before EV biomarkers can become reliable tools for cardiovascular diagnosis, prognosis, or disease monitoring.
Exploring extracellular vesicles as therapies
Extracellular vesicles may have applications beyond diagnosis. Because they naturally transport biological molecules between cells, researchers are investigating whether they can be adapted to deliver therapeutic cargo.
Stem cell-derived EVs are one area of interest. Rather than administering living stem cells, researchers may be able to use extracellular vesicles carrying some of the beneficial biological signals produced by those cells.
Engineered EVs provide another possibility. Scientists can potentially modify vesicles or load them with RNA and other therapeutic molecules, creating delivery systems designed to influence specific cells or biological pathways.
Challenges before clinical use
Despite their potential, several important questions remain.
Researchers need more reliable methods for controlling which molecules are loaded into EVs and determining where the vesicles travel after administration. Possible immune responses also need careful evaluation.
Manufacturing and regulatory standards present additional challenges. Extracellular vesicles are complex biological products, and consistent methods will be needed to isolate, characterize, manufacture, and test them before EV-based therapies can be widely evaluated clinically.
The researchers also catalog active clinical trials and identify areas where additional evidence is needed to move EV technologies closer to cardiovascular medicine.
Connecting EV biology with cardiovascular medicine
Extracellular vesicles occupy an unusual position in cardiovascular research because the same biological characteristics that make them messengers between cells could potentially be used for both diagnosis and treatment.
Their molecular cargo may provide biomarkers reflecting cardiovascular health, while their natural ability to transport biological molecules could be adapted for therapeutic delivery. Understanding these two roles, along with the mechanisms through which EVs connect the heart with other organs, could help researchers develop more precise approaches to cardiovascular disease.
