bims-evecad Biomed News
on Extracellular vesicles and cardiovascular disease
Issue of 2026–07–19
fourteen papers selected by
Cliff Dominy
  1. Human Extracellular Vesicles, Metabolites, and Metabolomics: A Comprehensive Review.
  2. Bioenergetics-Driven Extracellular Vesicle Therapies for Heart Failure: From Preclinical Insights to Regenerative Translation.
  3. Pathological regulation of endothelial-to-mesenchymal transition in cardiac fibrosis through signaling pathways and exosomal microRNA crosstalk.
  4. Exosome-nanomaterial hybrid nanomedicine for ischemic stroke: microenvironment-informed design, therapeutic applications, and translational challenges.
  5. Harnessing liver-heart crosstalk via extracellular vesicle-mediated hepatic delivery of microRNAs for cardiac repair.
  6. Salvianolic Acid B Upregulates miR-744-5p Expression in Peripheral Blood Mononuclear Cell-Derived Extracellular Vesicles to Alleviate Uremic Cardiomyopathy.
  7. Engineered extracellular vesicles for targeted TREX1 delivery attenuate neuroinflammation after cerebral ischemia.
  8. Extracellular Vesicles in Stroke: Drivers of Brain-Body Network Crosstalk.
  9. IL-12Rβ2 is Expressed in the Synthetic SMC and Detected in the Blood of Patients With Acute Myocardial Infarction.
  10. Beyond cardiac fibroblasts: research advances on understanding and targeting intercellular communication networks in cardiac fibrosis.
  11. Photobiomodulation-reprogrammed extracellular vesicles delivered via a biodegradable microneedle patch promote cardiac repair by enhancing glycolytic metabolism.
  12. VSIG3 preserves mitochondrial homeostasis and restrains CD4⁺ T-Cell infiltration in myocardial ischemia-reperfusion injury through regulation of mitochondrial-derived vesicles.
  13. Mesothelial cells derived extracellular vesicles promote angiogenesis through the transfer of angiopoietin-2.
  14. Atherosclerotic Cardiovascular Disease and Cancer.
  1. OMICS. 2026 Jul 14. 15578100261467517
    Human Extracellular Vesicles, Metabolites, and Metabolomics: A Comprehensive Review.
    Mohammed A Al-Zubaidi.
      Metabolomics is a powerful systems-level approach and has the potential to serve as an important part for understanding the biochemical pathways and metabolic phenotypes in physiological and pathological states. Extracellular vesicles (EVs), which include apoptotic bodies, microvesicles, and exosomes, have emerged alongside metabolomics as active mediators of intercellular communication, transporting diverse cargo that mirrors the cellular origin and metabolic status of their parent cell. EVs are enriched with lipids, proteins, nucleic acids, and biologically active metabolites involve in signal transduction, metabolic regulation, and pathogenic mechanisms of a disease. Nevertheless issues related to heterogeneity of vesicles, purity of isolation, and detection sensitivity of metabolites, the study of EV metabolomics still methodologically and analytically challenging. This review offers a critical synthesis of current knowledge in EV metabolomics including analytical technology, statistical and computational approaches, and emerging clinical applications. In addition, a specific focus on methodological variability, contamination chances, and limitations in existing research study design that affect reproducibility and translation. Furthermore, multi-omics integration and machine learning are reviewed as promising approaches to enhance the discovery of biomarkers and interpretation of the biological system. Finally, highlighting the key research gap and future research directions to steer the advancement of clinically related applications in translational medicine.
    Keywords:  biology systems; biomarkers; extracellular vesicles; extracellular vesicles challenges; metabolomics
    DOI:  https://doi.org/10.1177/15578100261467517
  2. Int J Mol Sci. 2026 Jun 29. pii: 5849. [Epub ahead of print]27(13):
    Bioenergetics-Driven Extracellular Vesicle Therapies for Heart Failure: From Preclinical Insights to Regenerative Translation.
    Dhienda C Shahannaz, Tadahisa Sugiura.
      Heart failure (HF) is fundamentally a disease of energetic insufficiency, in which impaired mitochondrial efficiency, maladaptive metabolic remodeling, and disrupted intercellular signaling converge at the organ level to limit cardiac performance. Despite advances in pharmacologic and device-based therapies, current treatment paradigms largely modulate hemodynamics or neurohormonal pathways rather than directly restoring myocardial bioenergetic capacity. Emerging evidence positions extracellular vesicles (EVs) as endogenous regulators of cardiac energy homeostasis, capable of orchestrating coordinated metabolic and mitochondrial adaptations across cardiac and non-cardiac cell populations. This review advances a system-level framework in which EVs are conceptualized as bioenergetic therapeutics, i.e., active biological agents that reprogram cellular energy utilization, substrate flexibility, and mitochondrial efficiency, rather than passive carriers of isolated molecular cargo. We synthesize preclinical evidence demonstrating EV-mediated modulation of oxidative phosphorylation, glycolytic balance, redox signaling, and mitochondrial dynamics, and examine how these effects scale from cellular and small-animal models to clinically relevant heart failure phenotypes. Importantly, we highlight organ-level integration, wherein EV signaling interfaces with vascular, immune, and metabolic networks to reshape myocardial energetic demand and supply. By bridging mechanistic insights with translational considerations, this review addresses the central question of how EV-driven bioenergetic reprogramming can be deployed within contemporary HF treatment paradigms. We propose EV-based strategies as complementary or synergistic interventions capable of restoring energetic resilience, reframing heart failure therapy beyond structural repair toward systemic metabolic renewal.
    Keywords:  cardiac bioenergetics; energetic insufficiency; extracellular vesicles; heart failure; intercellular energy signaling; metabolic remodeling; mitochondrial efficiency; organ-level metabolism; systems cardiology; translational therapeutics
    DOI:  https://doi.org/10.3390/ijms27135849
  3. Korean J Physiol Pharmacol. 2026 Jul 13.
    Pathological regulation of endothelial-to-mesenchymal transition in cardiac fibrosis through signaling pathways and exosomal microRNA crosstalk.
    Lan Phuong Phan, Kyung-Sun Heo.
      Cardiac fibrosis is a central pathological feature of many cardiovascular diseases and contributes to progressive myocardial remodeling and heart failure. Among the diverse cellular sources of activated fibroblasts, endothelial cells have emerged as a significant contributor through endothelial-to-mesenchymal transition (EndMT). During EndMT, endothelial cells lose their endothelial characteristics and acquire mesenchymal phenotypes, resulting in increased extracellular matrix deposition and tissue stiffening. Multiple pathological stimuli, including inflammatory signaling, oxidative stress, and metabolic dysregulation, activate intracellular signaling pathways that drive EndMT. In addition to these molecular mechanisms, recent studies highlight the importance of intercellular communication mediated by extracellular vesicles, particularly exosomes carrying microRNAs (miRNAs), in regulating cardiac fibrosis. Exosomal miRNAs released from endothelial cells, cardiomyocytes, and fibroblasts can modulate fibrotic signaling networks and influence EndMT progression. This review summarizes the pathological signaling pathways governing EndMT in cardiac fibrosis and discusses the emerging roles of exosomal miRNA-mediated crosstalk in cardiac remodeling. Understanding these integrated mechanisms may provide new insights into therapeutic strategies targeting cardiac fibrosis.
    Keywords:  Cardiac fibrosis; Endothelial-to-mesenchymal transition; Exosome; MicroRNA
    DOI:  https://doi.org/10.4196/kjpp.26.119
  4. Front Cell Neurosci. 2026 ;20 1835402
    Exosome-nanomaterial hybrid nanomedicine for ischemic stroke: microenvironment-informed design, therapeutic applications, and translational challenges.
    Qi Zhu, Xiaodan Wu.
      Ischemic stroke (IS) remains a major cause of mortality and long-term disability despite advances in reperfusion therapy, underscoring the need for adjunctive interventions that can operate within the dynamic post-ischemic microenvironment. Exosomes and other extracellular vesicles (EVs) provide a biologically compatible interface for brain delivery, yet native vesicles are constrained by heterogeneous composition, modest loading efficiency, limited targeting control, and manufacturing variability. Exosome-nanomaterial hybrid systems are therefore emerging as modular platforms that integrate exosomal biointerfaces with the tunable payload capacity, imaging compatibility, mechanical stability, and stimulus responsiveness of synthetic nanomaterials. In this review, we propose a microenvironment-informed design paradigm for IS nanomedicine. In this framework, the ischemic lesion is not treated as a passive delivery destination, but as a staged design brief defined by blood-brain barrier (BBB) remodeling, thromboinflammation, oxidative stress, immune-cell trafficking, and neurovascular repair. We summarize how exosome source, nanomaterial component, cargo loading, surface functionalization, administration route, and characterization strategy can be selected according to these pathological cues. We further discuss therapeutic applications in BBB-penetrant delivery, neuroprotection, inflammatory modulation, imaging-guided therapy, and neurovascular recovery, together with safety, quality-control, manufacturing, and regulatory barriers. Overall, exosome-nanomaterial hybrids may become clinically meaningful for IS only when their design is microenvironment-informed, mechanism-driven, and translationally scalable.
    Keywords:  blood–brain barrier; exosomes; extracellular vesicles; hybrid nanoparticles; ischemic stroke; nanomedicine; neurovascular repair; thromboinflammation
    DOI:  https://doi.org/10.3389/fncel.2026.1835402
  5. Clin Sci (Lond). 2026 Jul 13. pii: CS20250919. [Epub ahead of print]
    Harnessing liver-heart crosstalk via extracellular vesicle-mediated hepatic delivery of microRNAs for cardiac repair.
    Ji-Young Kang, Dasom Mun, Gyeongseo Yoo, Malgeum Park, Jaewoong Lee, Seyong Chung, Nuri Yun, Boyoung Joung.
      Extracellular vesicles (EVs) hold great potential to deliver microRNAs (miRNAs) in vivo; however, its preferential hepatic accumulation after systemic administration hinders the therapeutic efficacy of miRNAs. Inter-organ communication via endocrine factors is crucial for maintaining physiological homeostasis. Herein, this study leveraged liver-heart crosstalk to overcome the hepatic tropism of EVs and reframe it as a therapeutic advantage for cardiac injury. In a mouse model of angiotensin II (Ang II)-induced cardiac injury, liver tissues showed distinct changes in inflammation-related proteins compared with saline-treated controls, indicating hepatic involvement in cardiac injury. To establish a liver-heart crosstalk-based therapeutic approach, EV@miR-155 were prepared by loading miRNA-155 into mesenchymal stem cell-derived EVs. After intravenous administration, EV@miR-155 predominantly accumulated in the liver, increased hepatic miRNA-155 levels, and remodeled the hepatic microenvironment. This remodeling suppressed PPARα-mediated production of fibroblast growth factor 21 (FGF21), a hepatokine implicated in cardiac pathophysiology, thereby establishing a liver-heart crosstalk axis. Remarkably, EV@miR-155 treatment significantly improved cardiac function and reduced myocardial fibrosis and hypertrophy without inducing systemic toxicity (P < 0.05). Therefore, this study provides a conceptual shift by transforming the natural hepatic tropism of EVs-traditionally regarded as a delivery limitation-into a therapeutic route that enables liver-heart crosstalk-mediated cardiac repair.
    Keywords:  Cardioprotection; Extracellular vesicles; Hepatic tropism; Liver–heart crosstalk; MicroRNAs
    DOI:  https://doi.org/10.1042/CS20250919
  6. J Extracell Vesicles. 2026 Jul;15(7): e70331
    Salvianolic Acid B Upregulates miR-744-5p Expression in Peripheral Blood Mononuclear Cell-Derived Extracellular Vesicles to Alleviate Uremic Cardiomyopathy.
    Ziran Wang, Jiaojiao Hao, Yaxi Shang, Wenli Ma, Nan Wang, Weidong Wang, Qingzhu Tang, Xiangning Du, Fan Yang, Biaojie Qin, Shuni Chen, Kun Xiao, Longkai Li, Xianan Guo, Xin Qi, Shuang Meng, Huiyi Song, Hongli Lin.
      Uremic cardiomyopathy (UCM) is a severe complication of uraemia that lacks effective treatments. The role of immune dysfunction in haemodialysis patients with UCM remains unclear. Peripheral blood mononuclear cells (PBMCs) are major components of the immune system; however, they do not directly contact cardiomyocytes. In general, extracellular vesicles (EVs) function as intercellular communication mediators. Therefore, in this study, we first investigated the role of PBMC-derived EVs (PBMC-EVs) in UCM and identified EV-miR-744-5p as a key molecule involved in PBMC-cardiomyocyte communication. Mechanistically, indoxyl sulphate (IS) downregulated miR-744-5p expression in PBMC-EVs, leading to IGF2R upregulation in cardiomyocytes, thereby exacerbating myocardial injury via induction of hypertrophy, apoptosis and inflammatory pathway activation in the cardiomyocytes. We also explored the potential of natural products to treat UCM by modifying PBMC-EVs and found that the traditional Chinese medicine monomer salvianolic acid B (Sal B) could bind to YY1, enhancing miR-744-5p expression in PBMC-EVs and thus mitigating myocardial injury in UCM. Taken together, these findings indicate the critical role of PBMC-EVs in UCM and suggest the cardioprotective effects of Sal B via PBMC-EV modification. They also provide novel insights into immune mechanisms underlying UCM, particularly indicating that targeting PBMC-EVs may be a promising UCM treatment strategy.
    Keywords:  YY1; extracellular vesicles; miR‐744‐5p; peripheral blood mononuclear cells; salvianolic acid B; uremic cardiomyopathy
    DOI:  https://doi.org/10.1002/jev2.70331
  7. J Biomed Res. 2026 Jul 25. 1-16
    Engineered extracellular vesicles for targeted TREX1 delivery attenuate neuroinflammation after cerebral ischemia.
    Xiaorui Lei, Xinrong Lv, Yiran Wang, Xiao Liang, Yuyao Wu, Jiangjing Yan, Liqi Zheng, Kuiyuan Hou, Tian Tian.
      Ischemic stroke stands as a principal driver of global mortality and permanent functional deficits. Notably, the clinical efficacy of current interventions is severely restricted by post-ischemic neuroinflammation. Cerebral ischemic injury prompts an inflammatory surge mediated by the cGAS-STING signaling cascade, a process initiated by the recognition of aberrantly localized cytosolic DNA. Three-prime repair exonuclease 1 (TREX1), a cytosolic DNA exonuclease, negatively regulates STING signaling; however, efficient delivery of TREX1 to the ischemic brain remains a major challenge. Here, we engineered mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) as carriers for TREX1 delivery. This was accomplished by using a palmitoylation signal-fused construct (PALM-TREX1), which enables efficient loading of the protein into extracellular vesicles. The C1C2 domains of lactadherin and the RGD-4C peptide were combined into a single recombinant fusion protein, enabling EV surface functionalization for enhanced ischemic targeting via phosphatidylserine interaction. In a mouse model of middle cerebral artery occlusion (MCAO), RGD-modified TREX1-loaded EVs (RGD-EV-TREX1) preferentially accumulated in ischemic regions, suppressed STING pathway activation, and reduced microglial activation and pro-inflammatory cytokine expression. The reduction in neuronal DNA damage and apoptosis ultimately facilitated improved neurological functional recovery, positioning RGD-EV-TREX1 as a promising cell-free therapeutic strategy for ischemic stroke.
    Keywords:  TREX1; extracellular vesicles; ischemic stroke; targeted delivery
    DOI:  https://doi.org/10.7555/JBR.40.20260252
  8. Transl Stroke Res. 2026 Jul 13. pii: 77. [Epub ahead of print]17(4):
    Extracellular Vesicles in Stroke: Drivers of Brain-Body Network Crosstalk.
    Zhi-Ming Xu, Yu-Jia Jin, Wei-Qing Zhang, Xiang-Hua Ye, Feng Gao.
      Mounting evidence reframes stroke not as a single cerebral event but as a dynamic brain-body network disorder. Extracellular vesicles (EVs)-lipid bilayer-enclosed particles released by virtually all cells-serve as intercellular messengers that couple vascular injury, neuroinflammation, and systemic responses. EVs carry nucleic acids, proteins, and lipids reflective of their cellular sources and may reach the circulation and interface with the CNS via context-dependent routes, including blood-brain barrier (BBB) disruption and active transport mechanisms. This review integrates clinical and experimental evidence across vascular etiologies, intra-CNS communication, and systemic complications to outline how EV programs may encode and propagate stroke pathology. We further discuss emerging analytical standards, current clinical EV signatures, and translational frameworks-including how to distinguish stroke-specific signals from injury-generic responses-and outline trial designs to test whether modulating EV pathways can influence recovery trajectories.
    DOI:  https://doi.org/10.1007/s12975-026-01452-7
  9. Korean Circ J. 2026 Jun 02.
    IL-12Rβ2 is Expressed in the Synthetic SMC and Detected in the Blood of Patients With Acute Myocardial Infarction.
    Dong Hoon Kang, Hee Su Lee, Jin-Ah Yang, In Sook Kang, Sodam Jung, Kihwan Kwon, Sang Won Kang.
       BACKGROUND AND OBJECTIVES: De-differentiation and proliferation of smooth muscle cells (SMCs), triggered by pro-atherogenic factors or endothelial damage, contribute to progressive vascular remodeling. However, biomarkers reflecting the SMC phenotypic changes indicative of vulnerable plaques remain unavailable.
    METHODS: We characterized mRNA and protein expression of interleukin-12 receptor beta 2 subunit (IL-12Rβ2) in human aortic SMCs and human carotid arteries with atherosclerotic lesions by quantitative real-time polymerase chain reaction, immunoblotting, flow cytometry, and immunohistochemistry. Functional roles of IL-12Rβ2 were evaluated by siRNA-mediated knockdown in synthetic SMCs and a rat carotid balloon injury model. A capture enzyme-linked immunosorbent assay (ELISA) was developed to measure circulating IL-12Rβ2 levels in plasma from patients with acute coronary syndromes.
    RESULTS: The IL-12Rβ2 protein is about 2-fold higher in the thickened carotid arteries from patients with atherosclerosis than in normal arteries. The in vitro studies demonstrate that IL-12Rβ2 expression is induced in synthetic SMCs by interferon (IFN)-γ stimulation. The knockdown of IL-12Rβ2 significantly reduces proliferation, migration, and monocyte adhesion in synthetic SMCs and inhibits neointimal thickening in a rat carotid balloon injury model. IL-12Rβ2 is detected in SMC-derived extracellular vesicles (EVs) circulating in plasma from acute myocardial infarction (AMI) patients and is successfully quantified using a capture ELISA employing anti-PDGFRβ antibody as an SMC-specific marker.
    CONCLUSIONS: IL-12Rβ2, selectively induced in synthetic SMCs by IFN-γ, is released via EVs into blood in AMI patients, representing a novel biomarker to detect vulnerable atherosclerotic plaques through the newly-developed ELISA system.
    Keywords:  Biomarker; Extracellular vesicle; Interleukin-12 receptor beta 2 subunit; Myocardial infarction; Smooth muscle cells
    DOI:  https://doi.org/10.4070/kcj.2025.0330
  10. Front Cardiovasc Med. 2026 ;13 1858990
    Beyond cardiac fibroblasts: research advances on understanding and targeting intercellular communication networks in cardiac fibrosis.
    Xiduo Zhao, Lianyu Hua, Youjun Xiong, Fuyou Shi, Yilin Zhong, Shangwei Zhang, Chengnan Tian.
      Cardiac fibrosis is pivotal in the progression of various cardiovascular diseases, ultimately leading to heart failure. Traditionally, research has focused on the activation and transformation of cardiac fibroblasts. However, the heart's complexity, involving multiple cell types, means fibrosis is not driven by a single cell type but by a network of intercellular communication. This network includes signaling mediators from the pericardial space, a crucial regulatory compartment for intercellular cross-talk. This article reviews recent advances that surpass the traditional single-cell approach, providing an in-depth analysis of the complex networks involved in myocardial fibrosis. These networks encompass cardiomyocytes, endothelial cells, and immune cells like macrophages and T cells, which interact through paracrine signaling, direct cell-cell contact, and extracellular vesicle-mediated mechanisms. The review delves into the molecular mechanisms of these communication modes, clarifying the functional outcomes of each signaling pathway in fibrosis initiation and persistence. It also summarizes the phenotypic changes and functional impairments caused by abnormal intercellular crosstalk, such as excessive extracellular matrix deposition, myocardial stiffness, electrical signal disturbances, and cardiac contractile dysfunction. Additionally, the review examines the latest therapeutic strategies and potential intervention targets, focusing on specific cytokines, signaling pathways, or vesicular delivery systems. It discusses the translational value of preclinical findings, the limitations of single-target interventions, and the need for multi-target combined strategies. The article concludes with insights into core regulatory nodes and future optimization directions for anti-fibrotic therapy. This exploration aims to provide new theoretical foundations and directions for developing precise and effective anti-fibrotic therapies.
    Keywords:  extracellular vesicles; immune cells; intercellular communication; myocardial fibrosis; paracrine signaling; therapeutic targets
    DOI:  https://doi.org/10.3389/fcvm.2026.1858990
  11. Acta Pharm Sin B. 2026 Jul;16(7): 4592-4615
    Photobiomodulation-reprogrammed extracellular vesicles delivered via a biodegradable microneedle patch promote cardiac repair by enhancing glycolytic metabolism.
    Yining Liu, Sijia Li, Ao Cai, Wei Li, Wanyu Zhang, Tianlong Li, Manjie Zhang, Chenlu Liu, Wenya Ma, Yuqing Lin, Hanjing Li, Xinlu Gao, Zhongyu Ren, Hang Yu, Haoyu Ji, Xiuxiu Wang, Yang Yu, Xu Liu, Yifu Shen, Ye Tian, Faqian Li, Yu Liu, Zhenwei Pan, Baofeng Yang, Benzhi Cai.
      Stem cell-derived extracellular vehicles (EVs) hold great therapeutic potential for myocardial infarction (MI). However, the efficient production of EVs with high bioactivity remains a critical bottleneck limiting their clinical translation. Here, we demonstrate that conditioned photobiomodulation (PBM) with green light is capable of activating human embryonic stem cells (hESCs) to secrete more EVs with superior cardioprotective activity. These PBM-reprogrammed hESC-EVs improve cardiac recovery in a murine MI model by promoting cardiomyocyte proliferation and angiogenesis while inhibiting apoptosis. Notably, we validate that these EVs similarly enhance the survival and proliferation of human cardiomyocytes, underscoring their translational potential. Further analysis reveals that this benefit is due to the higher miR-423-3p content in reprogrammed hESC-EVs, which enhances glycolytic metabolism and restores mitochondrial function by regulating the ZBTB7A/PKM2 axis. Moreover, we synthesize a methacryloyl hydrogel microneedle patch with superior biocompatibility, biodegradability, and mechanical strength for loading hESC-EVs, and convey the patch to the infarcted heart via a modified delivery apparatus. This system ensures the precise and sustained delivery of EVs to ischemic myocardium, offering a potent treatment for MI. Collectively, this optical and biomaterials-based approach efficiently prepares EVs with higher cardioprotective activity, providing new therapeutic strategies for heart disease.
    Keywords:  Cardiac repair; Extracellular vesicle; Glycolysis metabolism; MicroRNA; Microneedle patch; Myocardial infarction; Photobiomodulation; Stem cell
    DOI:  https://doi.org/10.1016/j.apsb.2026.04.015
  12. J Nanobiotechnology. 2026 Jul 13.
    VSIG3 preserves mitochondrial homeostasis and restrains CD4⁺ T-Cell infiltration in myocardial ischemia-reperfusion injury through regulation of mitochondrial-derived vesicles.
    Jian Hou, Liqun Shang, Zi Yan, Yuanhan Ao, Wanying Chen, Pei Lin, Jiarui Liu, Xintong Wang, Zhaojin Li, Huayang Li, Quan Liu, Yi Zhang, Jianping Yao, Can Gao, Junyou Zhu, Shiyu Li, Suiqing Huang, Zhongkai Wu.
      Myocardial ischemia-reperfusion (MI/R) injury remains an inevitable and severe clinical challenge during cardiac surgery, primarily characterized by mitochondrial dysfunction and robust CD4+ T cell infiltration. In this study, we investigated the therapeutic potential of the immune checkpoint molecule VSIG3 (V-set and transmembrane domain-containing protein 3) in mitigating MI/R injury. In clinical samples, ELISA-detectable VSIG3-related plasma immunoreactivity of an undefined molecular form was associated with myocardial injury and inflammation. Recombinant VSIG3 administration improved cardiac function in MI/R mice and was accompanied by lower cardiac extracellular vesicle (EV) levels, including a reduction in TOMM20⁺ mitochondrial-derived vesicle (MDV)-related signals. In vitro, VSIG3 attenuated apoptosis, enhanced antioxidant capacity, and preserved mitochondrial metabolism, accompanied by an associated increase in PI3K/Akt/mTOR phosphorylation at 3 h post-injury. Exogenous MDV supplementation partially counteracted the cytoprotective effects observed with VSIG3 treatment. In vivo, VSIG3 treatment reduced CD4+ T cell infiltration and suppressed inflammatory cytokines (TNF-α, IL-17α, IL-21) in myocardial tissue. In summary, exogenous MDVs behaved as detrimental stimuli in the present experimental settings, whereas VSIG3 treatment was accompanied by reduced MDV release, improved mitochondrial homeostasis, and suppressed T-cell activation. These findings support an association between VSIG3 treatment and MDV-related changes in MI/R injury, but do not establish MDV suppression as a necessary or sufficient mediator of VSIG3-mediated cardioprotection.
    Keywords:  CD4+ T-Cell; Extracellular vesicles; Mitochondrial dysfunction; Myocardial ischemia-reperfusion; PI3K/Akt/mTOR; VSIG3
    DOI:  https://doi.org/10.1186/s12951-026-04766-8
  13. PLoS One. 2026 ;21(7): e0353115
    Mesothelial cells derived extracellular vesicles promote angiogenesis through the transfer of angiopoietin-2.
    Shelly Loewenstein, Fabian Gerstenhaber, Sapir Milshtain, Stav Leibou, Omri Rahamimov, Alison Siegel, Hannah Sherman, Osnat Sher, Guy Lahat.
       BACKGROUND: Peritoneal mesothelial cells play a critical role in shaping the peritoneal tumor microenvironment and are increasingly recognized as active regulators of angiogenesis in cancers that metastasize to the peritoneum, including gastrointestinal (GI) and ovarian malignancies. Through complex interactions with tumor and stromal cells, peritoneal mesothelial cells contribute to the establishment of a pre-metastatic niche in the peritoneal cavity. Extracellular vesicles (EVs), nanosized vesicles secreted by most cell types, mediate intercellular communication by transferring bioactive molecules such as proteins, lipids, and nucleic acids. While tumor-derived EVs have been extensively studied in cancer progression, the role of mesothelial cells-derived EVs in regulating endothelial function and angiogenesis remains largely unexplored.
    METHODS: EVs were isolated from conditioned media of mesothelial cells and characterized before functional assays. Their effects on endothelial cell behavior were assessed using proliferation, migration, and invasion assays, as well as Matrigel-based tube formation and in vivo angiogenesis plug models. A proteome profiler angiogenesis array was used to identify enriched pro-angiogenic mediators. Mechanistic studies were conducted using lentiviral knockdown and overexpression strategies.
    RESULTS: Endothelial cells efficiently internalized mesothelial cells-derived EVs, leading to significant increases in proliferation, migration, invasion, and angiogenesis in vitro and in vivo. Proteomic profiling identified 43 angiogenic regulators within mesothelial cells-derived EVs, with angiopoietin-2 (ANG2) emerging as a key effector. Functional analyses demonstrated that mesothelial cells-derived EVs-induced angiogenesis was mediated through ANG2-TIE2 signaling, with subsequent activation of PI3K, Akt, and ERK1/2 pathways. Importantly, inhibition of ANG2 markedly reduced these angiogenic effects.
    CONCLUSIONS: This work establishes that EVs secreted by mesothelial cells promote angiogenesis by reprogramming endothelial cells through ANG2-dependent signaling. These findings uncover a novel mechanism of mesothelial-endothelial communication and highlight the ANG2 pathway as a promising therapeutic target in advanced GI cancers with peritoneal metastasis.
    DOI:  https://doi.org/10.1371/journal.pone.0353115
  14. Immunol Rev. 2026 Jul;340(1): e70141
    Atherosclerotic Cardiovascular Disease and Cancer.
    Anaïs Amend, Hauke Horstmann, Kory J Lavine, Chiara Giannarelli, Kathryn J Moore.
      Atherosclerotic cardiovascular disease (ASCVD) and cancer are increasingly recognized as interconnected diseases linked by shared immune mechanisms rather than merely overlapping risk factors. Common exposures such as smoking, obesity, diabetes, and dyslipidemia, together with aging and clonal hematopoiesis of indeterminate potential (CHIP), establish a chronic inflammatory milieu that drives both pathologies through coordinated reprogramming of myeloid and lymphoid compartments. Within this framework, a forward cardio-oncology axis is increasingly recognized, in which cancer therapies including chemotherapies, radiation, and immune checkpoint inhibitors induce cardiovascular injury, manifesting as cardiomyopathy, accelerated atherosclerosis, and immune-mediated myocarditis. Complementing this, a reverse axis has emerged in which cardiovascular injury states such as myocardial infarction, ischemia, and heart failure actively promote cancer initiation and progression through hematopoietic remodeling, extracellular vesicle-mediated communication, cardiac-derived factors, and immunosuppressive myeloid bias. At the tissue level, immune checkpoint pathways including PD-1, PD-L1, CTLA-4, LAG-3, and TIM-3 form spatially organized regulatory networks within atherosclerotic plaques. Their therapeutic perturbation restores T cell activity but may disrupt local immune homeostasis and promote plaque instability. In parallel, inflammatory cytokines such as IL-1β, IL-6, and TNF-α, often amplified by CHIP-associated clones, provide a mechanistic bridge linking atherogenesis with tumor immune evasion. Together, these observations support a unified view of ASCVD and cancer as immune-driven diseases connected by bidirectional axes of interaction. This review integrates emerging mechanistic and clinical evidence and outlines how immune-based stratification and targeted modulation of inflammation may enable more precise management of patients at the intersection of cardiovascular disease and cancer.
    Keywords:  atherosclerosis; cardio‐oncology; clonal hematopoiesis; extracellular vesicles; immune checkpoints; reverse cardio‐oncology; trained immunity
    DOI:  https://doi.org/10.1111/imr.70141
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