bims-evecad 2026-04-12 papers

bims-evecad

Biomed News

on Extracellular vesicles and cardiovascular disease

Issue of 2026–04–12
seven papers selected by
Cliff Dominy

Caveolin in extracellular vesicles: orchestrating interorgan communication in diabetes-associated cardiovascular disease☆.
Hypoxia conditioned adipose-derived stem cell-derived extracellular vesicle therapy improves cardiac function in a rat model of ischemic cardiomyopathy.
Mitochondrial Transfer: From Bench to Bedside.
Mitochondria-Derived Vesicles and Mitochondrial Extracellular Vesicles in Health and Cardiovascular Disease.
EVs-Mediated Intracardiac Crosstalk Mitigates Doxorubicin-Induced Cardiotoxicity.
Extracellular vesicles as orchestrators of arterial and venous thrombosis: A unified mechanistic model.
MicroRNA, MicroRNA-lncRNA and MicroRNA-Circular RNA axes, and exosomal MicroRNAs: driving exercise-induced cardioprotection in heart failure.

Curr Opin Physiol. 2025 Dec;pii: 100862. [Epub ahead of print]46

Caveolin in extracellular vesicles: orchestrating interorgan communication in diabetes-associated cardiovascular disease☆.

Zhijun Meng, Mary K Sewell-Loftin, Vinoy Thomas, Xinliang Ma, Yajing Wang.

Small extracellular vesicles (sEVs) have been recognized as critical mediators of intercellular communication, impacting processes such as inflammation, tissue repair, and cardiovascular disease progression. Conventionally, research has focused on the general role of sEVs in mediating the signals among cell-cell communication without specifically considering the underlying molecular regulators. However, recent insights highlight the emerging importance of Caveolin, a protein integral to the formation of caveolae, in the regulation of EV biogenesis and release, particularly exosomes. This review underscores the novel role of Caveolin in sEV in shaping interorgan communication via sEV-mediated signaling and how it alters the cardiovascular disease development via modulating multiple pathways. These causes of sEVs transport crucial signaling molecules, including small RNAs and proteins, capable of modulating disease progression positively or negatively. Furthermore, we emphasize novel developments regarding Caveolin-1's influence on diabetes-related cardiovascular pathologies and metabolic disturbances, specifically insulin secretion, insulin signaling, insulin resistance, oxidative stress, and diabetes-associated complications. By bridging traditional views with recent advancements, this review seeks to provide a comprehensive understanding of Caveolin-1's potential as a therapeutic target in cardiovascular and metabolic disorders.

DOI: https://doi.org/10.1016/j.cophys.2025.100862
Regen Ther. 2026 Jun;32 101105

Hypoxia conditioned adipose-derived stem cell-derived extracellular vesicle therapy improves cardiac function in a rat model of ischemic cardiomyopathy.

Kunitaka Kumagai, Takuji Kawamura, Kosuke Torigata, Akima Harada, Yuichiro Kishimoto, Shigeru Miyagawa, Yasushi Yoshikawa.

   Introduction: Extracellular vesicles (EVs) are potential cell-free therapies for cardiac regeneration. Although adipose-derived stem cells (ADSCs) are easily obtained using minimally invasive procedures, therapeutic effects of hypoxically conditioned ADSC-derived EVs on the heart remain unknown. We aimed to verify whether hypoxic preconditioning enhances the therapeutic efficacy of ADSC-derived EVs.
Methods: Lewis female rats were used to isolate ADSCs and establish an ICM rat model. ADSCs were cultured in a 48-h exosome-free medium under 5% or 20% O2, and EVs were recovered using polyethylene glycol and ultracentrifugation. An MI model was created by ligating the left anterior descending artery via mini thoracotomy; EF<45% was confirmed 2 weeks later. Rats were randomly assigned to three groups (PBS, normoxic EV, and hypoxic EV groups), each undergoing mini thoracotomy and myocardial injection. Echocardiography was performed at 2- and 4-weeks post-administration to evaluate cardiac function, and histological analysis of fibrosis and angiogenesis was performed at 4 weeks. We performed miRNA sequencing on both EVs and RNA sequencing on the myocardium 2 days after administration.
Results: Functional analysis of EV microRNAs suggested that hypoxia increased levels of miRNAs involved in suppressing fibrosis. Echocardiography at 2 and 4 weeks post-EV administration showed greater improvement in cardiac function (reduction in diastolic and systolic diameters, and improvement in left ventricular EF) in the hypoxic ADSC-derived EV group. Fibrosis reduced and vascularization increased in the hypoxic ADSC-derived EV group tissues. On day 2 after hypoxic ADSC-derived EV administration, RNA sequencing of myocardial infarction border zones showed increased expression of multiple genes associated with antifibrotic, anti-inflammatory, and angiogenic processes in the heart. GSEA identified increased expression of acute inflammatory responses.
Conclusions: Hypoxic ADSC-derived EV administration induces acute inflammation and suppresses late-stage fibrosis by modulating immunity, thereby contributing to improved cardiac function. They may be an effective option for cardiac regenerative therapy.

Keywords:  Extracellular vesicles; Ischemic cardiomyopathy; Left ventricular ejection fraction; microRNA

DOI:  https://doi.org/10.1016/j.reth.2026.101105
Circ Res. 2026 Apr 10. 138(8): e326984

Mitochondrial Transfer: From Bench to Bedside.

Gentaro Ikeda, Jiwen Li, Alyssa Wang, Amogha Medha Paleru, Phillip C Yang.

  Intercellular mitochondrial transfer has emerged as a fundamental mechanism of tissue adaptation and repair in the cardiovascular system, with major implications for cardiovascular, neurological, metabolic, and inflammatory diseases. Once thought to be static, mitochondria are now recognized as mobile organelles that move between cells via tunneling nanotubes, extracellular vesicles, and free mitochondria. These pathways support 2 complementary axes of mitochondrial communication: Rescue by Replenish, in which healthy mitochondria or mitochondrial components restore bioenergetics and stress resistance in recipient cells, and Relief by Release, in which damaged mitochondria are exported for degradation to preserve homeostasis and limit inflammation. We summarize the molecular machinery governing tunneling nanotube formation, mitochondria-derived vesicle biogenesis, extracellular vesicle sorting, and free mitochondrial release and uptake, and discuss how these processes shape organ function. Building on these mechanistic insights, we outline 4 translational strategies: (1) cell-based therapies that donate healthy mitochondria or scavenge damaged ones; cell-free approaches using (2) mitochondria-containing extracellular vesicles or (3) purified mitochondria; (4) pharmacological, nutritional, and lifestyle interventions that augment endogenous mitochondrial turnover and intercellular exchange. Finally, we discuss key barriers to clinical translation, including inflammatory and oncogenic risks, mitonuclear incompatibility, incomplete understanding of the fate and durability of transferred mitochondria, and the lack of standardized manufacturing, potency assays, and long-term storage methods. Continued integration of mechanistic biology with bioengineering and regulatory science will be essential to safely move mitochondrial transfer-based therapies from bench to bedside in cardiovascular medicine.

Keywords:  cell communication; energy metabolism; extracellular vesicles; homeostasis; inflammation; mitochondria; nanotubes

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326984
Circ Res. 2026 Apr 10. 138(8): e327357

Mitochondria-Derived Vesicles and Mitochondrial Extracellular Vesicles in Health and Cardiovascular Disease.

Erjola Rapushi, Anubhav Aryal, Tianyuan Yang, Zhixin Li, Xiaohong Wang, Guo-Chang Fan.

  Mitochondria-derived vesicles (MDVs) and mitochondrial extracellular vesicles (mitoEVs) represent 2 related extensions of mitochondrial dynamics that link organelle maintenance to communication within and between cells. MDVs are small vesicles that bud directly from mitochondria, selectively packaging components of the outer membrane, inner membrane, or matrix. They serve as a localized quality control mechanism that removes oxidized or damaged material without engaging the entire mitophagic machinery. After budding, MDVs typically enter the endolysosomal pathway, where they can fuse with late endosomes or lysosomes for cargo degradation. A subset of MDVs also targets other organelles, particularly peroxisomes, contributing to organelle crosstalk, lipid metabolism, and redox balance. By contrast, mitoEVs released into the extracellular space contain intact functional mitochondria, mitochondrial contents (proteins, DNAs/RNAs, lipids, and so on), and nonmitochondrial cargo (ie, mRNAs, noncoding RNAs, and so on), which can be transferred to recipient cells and subsequently induce either pathogenic or beneficial outcomes. Therefore, mitoEVs have been implicated in metabolic cooperation, immune regulation, tissue remodeling, and aging. Accordingly, this review summarizes recent progress on the diverse mechanisms for the biogenesis of MDVs and mitoEVs, as well as available protocols for their isolation. The roles of MDVs and mitoEVs in mediating mitochondrial quality/quantity control and multiple layers of crosstalk between intracellular organelles and different cell types in health and disease are highlighted. Last, mitoEV-mediated pathogenic effects and therapeutic potential in cardiovascular disease are also discussed.

Keywords:  cardiovascular diseases; extracellular vesicles; lipid metabolism; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327357
Circ Res. 2026 Apr 08.

EVs-Mediated Intracardiac Crosstalk Mitigates Doxorubicin-Induced Cardiotoxicity.

Hongyun Wang, Yiqing Chen, Tianhui Wang, Xuan Ye, Xiao Zhang, Yuling Xie, Jinxin Xie, Qianwen Wu, Zilin Guo, Xiaoying Yang, Chang Liu, Lunan Wang, Guangpeng Li, Dongchao Lu, Priyanka Gokulnath, H Immo Lehmann, Guoping Li, Yuxiang Dai, Dragos Cretoiu, Joost P G Sluijter, Junjie Xiao.

   BACKGROUND: Extracellular vesicles (EVs) are involved in exercise-induced cardiac protection. However, the effects and underlying mechanisms of tissue-specific molecular cargo packaged within these EVs, including PIWI-interacting RNA (piRNA), remain poorly understood. In particular, the mechanistic contribution of exercised intracardiac EV-associated piRNAs to doxorubicin-induced cardiotoxicity (DCT) has not been defined.
METHODS: Transgenic reporter mice and a cardiomyocyte-specific Rab27a knockout strategy were used to investigate the contribution of cardiomyocyte-derived EVs to exercise-induced cardioprotection against DCT. To screen functionally relevant cardioprotective piRNA cargo, heart tissues from patients with dilated cardiomyopathy and experimental DCT models were analyzed, including cardiomyocyte-specific knockout mice, human induced pluripotent stem cell-derived cardiomyocytes, and primary murine cardiomyocytes.
RESULTS: We found that cardiomyocyte-derived EVs post-exercise were enriched for a cardiac-specific protective piRNA (piR-mmu-57256903), designated as an exercise-induced protective piRNA (EPPIR). EPPIR levels were significantly reduced in heart tissue from patients with dilated cardiomyopathy and DCT models. Functionally, EPPIR protects the heart against DCT by regulating KDM1 KDM6B (lysine [K]-specific demethylase 6B)-H3K27me3-Dtna epigenetic axis. In addition, EPPIR acts as a cardiomyocyte-specific suppressor of Tp53 (tumor protein p53).
CONCLUSIONS: We identify a previously unrecognized role for cardiomyocyte-derived EV-associated piRNA EPPIR in mediating exercise-induced cardioprotection. EPPIR exerts its protective effects through coordinated regulation of the KDM6B-Dtna axis and cardiomyocyte-specific suppressor of Tp53, providing mechanistic insight and highlighting a potential therapeutic strategy for DCT.

Keywords:  doxorubicin; exercise; extracellular vesicles; heart failure; myocytes, cardiac

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327827
Vascul Pharmacol. 2026 Apr 02. pii: S1537-1891(26)00025-X. [Epub ahead of print]163 107605

Extracellular vesicles as orchestrators of arterial and venous thrombosis: A unified mechanistic model.

Chunlan Xia, Chenqin Xu, Yumiao Liu, Xia Feng, Yi Le, Hongtao Xu, Fei Qi, Zhiqiang Liang, Jian Chen, Ji Li.

  Extracellular vesicles (EVs) function as the central mechanobiological orchestrators connecting vascular inflammation and hemostasis. In this review, we propose a unified mechanistic model wherein EV thrombogenicity is governed by convergent catalytic switches: phosphatidylserine (PS) externalization, which scaffolds tenase and prothrombinase assembly, and the structural "decryption" of Tissue Factor (TF) via membrane reorganization and thiol-disulfide exchange. While these molecular drivers are universal, their pathological manifestations diverge strictly by hemodynamic context. In the high-shear arterial environment, EVs act as stress transducers; platelet-EVs leverage von Willebrand factor-GPIb interactions to drive acute occlusion. Conversely, under venous stasis, an immunothrombotic axis dominates; here, hypoxic endothelial- and leukocyte-EVs shuttle mitochondrial DAMPs to potentiate Neutrophil Extracellular Trap (NET) formation, scaffolding the fibrin-rich "red thrombus." Despite this mechanistic clarity, clinical translation is impeded by methodological constraints, particularly the confounding interference of lipoproteins (e.g., chylomicrons) in functional assays. Ultimately, harnessing EVs as "liquid biopsy" biomarkers or therapeutic vectors requires a paradigm shift from particle enumeration to functional phenotyping, alongside rigorous safety engineering to resolve the inherent thrombogenic paradox of EV-based interventions.

Keywords:  Biomarkers; Clinical translation; Extracellular vesicles; Immunothrombosis; Thromboembolism

DOI:  https://doi.org/10.1016/j.vph.2026.107605
Front Cell Dev Biol. 2026 ;14 1767057

MicroRNA, MicroRNA-lncRNA and MicroRNA-Circular RNA axes, and exosomal MicroRNAs: driving exercise-induced cardioprotection in heart failure.

Yang Li, Junmin Wang, De Ma, Jinpeng He.

  Regular physical activity is a powerful non-pharmacological strategy for preventing and managing cardiovascular diseases (CVDs), including heart failure, by promoting cardioprotective adaptations through molecular mechanisms that remain incompletely elucidated. This review explores the central role of non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), in exercise-induced cardioprotection, highlighting their interactions within miRNA-lncRNA and miRNA-circRNA axes, as well as the function of exosomal miRNAs as key exerkines facilitating inter-organ crosstalk. Synthesizing current literature, we examine ncRNA biogenesis, canonical functions, and exercise-responsive profiles, focusing on pivotal miRNAs such as miR-1, miR-133, miR-21, miR-126, miR-29, miR-208a, and miR-499; lncRNA-miRNA networks including MALAT1/miR-150-5p, H19/miR-139, and GAS5/miR-217; circRNA-miRNA interactions like circUtrn/miR-132/212; and exosomal miRNAs derived from skeletal muscle (e.g., miR-130a, miR-1), brown adipose tissue (e.g., miR-17-3p), endothelium (e.g., miR-126), and cardiomyocytes (e.g., miR-21-3p). These elements are evaluated in models of physiological cardiac remodeling, myocardial infarction, ischemia-reperfusion injury, diabetic cardiomyopathy, and heart failure, with consideration of influencing factors such as sex, age, and training modality. Exercise-modulated miRNAs differentiate benign "athlete's heart" from pathological hypertrophy by governing angiogenesis, fibrosis, metabolic shifts, and arrhythmia risk, while lncRNA-miRNA and circRNA-miRNA axes regulate apoptosis, inflammation, mitochondrial dynamics, and extracellular matrix remodeling in CVD contexts. Exosomal miRNAs enable remote protection by activating survival, angiogenic, and anti-fibrotic pathways via signaling cascades like PI3K/AKT and NF-κB. Responses exhibit variability based on demographic and exercise variables, underscoring ncRNAs' promise as diagnostic biomarkers, therapeutic targets, or mimics of exercise benefits for heart failure management.

Keywords:  MicroRNAs; biomarkers; cardioprotection; circular RNAs; exercise; exerkines; exosomes; long non-coding RNAs

DOI:  https://doi.org/10.3389/fcell.2026.1767057