The role of extracellular vesicles in cancer.
Cell
Intercellular communication is a key feature of cancer progression and metastasis. Extracellular vesicles (EVs) are generated by all cells, including cancer cells, and recent studies have identified EVs as key mediators of cell-cell communication via packaging and transfer of bioactive constituents to impact the biology and function of cancer cells and cells of the tumor microenvironment. Here, we review recent advances in understanding the functional contribution of EVs to cancer progression and metastasis, as cancer biomarkers, and the development of cancer therapeutics.
10.1016/j.cell.2023.03.010
In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo: Part II: Pathology: Part II: Pathology.
Journal of extracellular vesicles
It is clear from Part I of this series that extracellular vesicles (EVs) play a critical role in maintaining the homeostasis of most, if not all, normal physiological systems. However, the majority of our knowledge about EV signalling has come from studying them in disease. Indeed, EVs have consistently been associated with propagating disease pathophysiology. The analysis of EVs in biofluids, obtained in the clinic, has been an essential of the work to improve our understanding of their role in disease. However, to interfere with EV signalling for therapeutic gain, a more fundamental understanding of the mechanisms by which they contribute to pathogenic processes is required. Only by discovering how the EV populations in different biofluids change-size, number, and physicochemical composition-in clinical samples, may we then begin to unravel their functional roles in translational models in vitro and in vivo, which can then feedback to the clinic. In Part II of this review series, the functional role of EVs in pathology and disease will be discussed, with a focus on in vivo evidence and their potential to be used as both biomarkers and points of therapeutic intervention.
10.1002/jev2.12190
Targeting endothelial exosomes for the prevention of cardiovascular disease.
Jia Guanghong,Sowers James R
Biochimica et biophysica acta. Molecular basis of disease
Exosomes are small lipid bilayer-enclosed 30-140 nm diameter vesicles formed from endosomes. Exosomes are secreted by various cell types including endothelial cells, immune cells and other cardiovascular tissues, and they can be detected in plasma, urine, cerebrospinal fluid, as well as tissues. Exosomes were initially regarded as a disposal mechanism to discard unwanted materials from cells. Recent studies suggest that exosomes play an important role in mediating of intercellular communication through the delivery and transport of cellular components such as nucleic acids, lipids, and proteins and thus regulate cardiovascular disease. Further, the underlying mechanisms by which abnormally released exosomes promote cardiovascular disease are not well understood. This review highlights recent studies involving endothelial exosomes, gives a brief overview of exosome biogenesis and release, isolation and identification of exosomes, and provides a contemporary understanding of the endothelial exosome pathophysiology and potential therapeutic strategies.
10.1016/j.bbadis.2020.165833
Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2/3-MAPK Signaling to Trigger Spontaneous Aortic Dissection.
Circulation
BACKGROUND:Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive. METHODS:Smooth muscle cell-specific and endothelial cell-specific Best3 knockout mice (Best3 and Best3, respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels. RESULTS:Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3 but not Best3 mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2/3 prevented AD progression in angiotensin II-infused Best3 and ApoE mice. CONCLUSIONS:These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2/3 degradation. Best3-MEKK2/3 signaling represents a novel therapeutic target for AD.
10.1161/CIRCULATIONAHA.122.063029
Endothelial HDAC1-ZEB2-NuRD Complex Drives Aortic Aneurysm and Dissection Through Regulation of Protein S-Sulfhydration.
Circulation
BACKGROUND:Aortic aneurysm and aortic dissection (AAD) are life-threatening vascular diseases, with endothelium being the primary target for AAD treatment. Protein S-sulfhydration is a newly discovered posttranslational modification whose role in AAD has not yet been defined. This study aims to investigate whether protein S-sulfhydration in the endothelium regulates AAD and its underlying mechanism. METHODS:Protein S-sulfhydration in endothelial cells (ECs) during AAD was detected and hub genes regulating homeostasis of the endothelium were identified. Clinical data of patients with AAD and healthy controls were collected, and the level of the cystathionine γ lyase (CSE)/hydrogen sulfide (HS) system in plasma and aortic tissue were determined. Mice with EC-specific CSE deletion or overexpression were generated, and the progression of AAD was determined. Unbiased proteomics and coimmunoprecipitation combined with mass spectrometry analysis were conducted to determine the upstream regulators of the CSE/HS system and the findings were confirmed in transgenic mice. RESULTS:Higher plasma HS levels were associated with a lower risk of AAD, after adjustment for common risk factors. CSE was reduced in the endothelium of AAD mouse and aorta of patients with AAD. Protein S-sulfhydration was reduced in the endothelium during AAD and protein disulfide isomerase (PDI) was the main target. S-sulfhydration of PDI at Cys343 and Cys400 enhanced PDI activity and mitigated endoplasmic reticulum stress. EC-specific CSE deletion was exacerbated, and EC-specific overexpression of CSE alleviated the progression of AAD through regulating the S-sulfhydration of PDI. ZEB2 (zinc finger E-box binding homeobox 2) recruited the HDAC1-NuRD complex (histone deacetylase 1-nucleosome remodeling and deacetylase) to repress the transcription of , the gene encoding CSE, and inhibited PDI S-sulfhydration. EC-specific HDAC1 deletion increased PDI S-sulfhydration and alleviated AAD. Increasing PDI S-sulfhydration with the HS donor GYY4137 or pharmacologically inhibiting HDAC1 activity with entinostat alleviated the progression of AAD. CONCLUSIONS:Decreased plasma HS levels are associated with an increased risk of aortic dissection. The endothelial ZEB2-HDAC1-NuRD complex transcriptionally represses , impairs PDI S-sulfhydration, and drives AAD. The regulation of this pathway effectively prevents AAD progression.
10.1161/CIRCULATIONAHA.122.062743
Current options and recommendations for the use of thoracic endovascular aortic repair in acute and chronic thoracic aortic disease: an expert consensus document of the European Society for Cardiology (ESC) Working Group of Cardiovascular Surgery, the ESC Working Group on Aorta and Peripheral Vascular Diseases, the European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the ESC and the European Association for Cardio-Thoracic Surgery (EACTS).
Czerny Martin,Pacini Davide,Aboyans Victor,Al-Attar Nawwar,Eggebrecht Holger,Evangelista Arturo,Grabenwöger Martin,Stabile Eugenio,Kolowca Maciej,Lescan Mario,Micari Antonio,Muneretto Claudio,Nienaber Christoph,de Paulis Ruggero,Tsagakis Konstantinos,Rylski Bartosz,Braverman Alan C,Di Marco Luca,Eagle Kim,Falk Volkmar,Gottardi Roman
European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery
Since its clinical implementation in the late nineties, thoracic endovascular aortic repair (TEVAR) has become the standard treatment of several acute and chronic diseases of the thoracic aorta. While TEVAR has been embraced by many, this disruptive technology has also stimulated the continuing evolution of open surgery, which became even more important as late TEVAR failures do need open surgical correction justifying the need to unite both treatment options under one umbrella. This fact shows the importance of-in analogy to the heart team-aortic centre formation and centralization of care, which stimulates continuing development and improves outcome . The next frontier to be explored is the most proximal component of the aorta-the aortic root, in particular in acute type A aortic dissection-which remains the main challenge for the years to come. The aim of this document is to provide the reader with a synopsis of current evidence regarding the use or non-use of TEVAR in acute and chronic thoracic aortic disease, to share latest recommendations for a modified terminology and for reporting standards and finally to provide a glimpse into future developments.
10.1093/ejcts/ezaa268
Retrograde type A dissection in the Vascular Quality Initiative thoracic endovascular aortic repair for dissection postapproval project.
Journal of vascular surgery
BACKGROUND:Retrograde dissection (RD) can be a serious complication after thoracic endovascular aortic repair (TEVAR), with retrograde type A dissection (RTAD) particularly life-threatening. Prior studies have suggested that treatment timing, anatomic characteristics, device selection, and procedural conduct of TEVAR performed for type B aortic dissection could mitigate the occurrence of RD. The Vascular Quality Initiative TEVAR for Dissection Registry is an ongoing project meant to satisfy Food and Drug Administration requirements for postmarket approval surveillance of the Gore conformable TAG thoracic endoprosthesis (W.L. Gore & Associates, Flagstaff, Ariz), Medtronic Valiant thoracic stent graft (Medtronic, Santa Rosa, Calif), and Cook Medical dissection devices (Cook Medical, Bloomington, Ind) and provides a unique source of evaluation for RTAD in a prospectively collected real-world registry. METHODS:A total of 588 consecutive patients at 49 institutions had undergone TEVAR for acute (<30 days; n = 336) and chronic (≥30 days; n = 252) type B aortic dissection were included. The occurrence of RD as reported by the participating centers and de-identified source documents were reviewed and confirmed independently by two of us (A.W.B. and G.W.). The demographics, procedural and device data, and anatomic considerations were evaluated, and the devices were grouped in a de-identified manner as Gore, Medtronic, and other. RESULTS:The mean follow-up was 889 days (median, 658 days), and 408 patients had completed follow-up data available for >1 year. A total of 19 patients with RD (3.2%) were identified, 9 of whom had been treated for acute and 10 for chronic dissection, a 2.7% and 4.0% incidence, respectively (P = .48, acute vs chronic). Of the 19 RD cases, 15 were RTAD, 6 after treatment of acute and 9 after treatment of chronic dissection, a 1.8% and 3.6% incidence, respectively (P = .19, acute vs chronic). Five cases of RD had occurred intraoperatively (four of which were RTAD). The median time to RD and RTAD was 62 and 69 days, respectively (range, 0 to 1600 days). Of the 15 patients with RTAD, 12 had undergone surgical repair and 2 had not undergone repair; the treatment of one was unknown. The overall mortality was 33.3% (5 of 15). The factors associated with RTAD included more extensive dissection (mean, 5.6 zones without RTAD vs 8.5 zones with RTAD; P = .001), female sex (28.3% female without RTAD vs 53.3% with RTAD; P = .04), and non-White race (62.7% White without RTAD vs 33.3% White with RTAD; P = .05). Mean oversizing was not significantly different for those without RTAD compared with that for those with RTAD (14.0% vs 14.2%; P = .92). The device type was anonymized in this project; however, we found no significant differences between the Gore, Medtronic, and all other devices. CONCLUSIONS:The rate of RD in the present real-world postapproval project was consistent with that from previously reported studies, including highly controlled pivotal studies. Device type was not predictive of RD, and the newly identified risk factors for RTAD include more extensive dissection and a trend toward a greater risk for female sex and non-White race.
10.1016/j.jvs.2021.11.075
Aortic Dissection: A Review of the Pathophysiology, Management and Prospective Advances.
Current cardiology reviews
Aortic dissection is an emergent medical condition, generally affecting the elderly, characterized by a separation of the aortic wall layers and subsequent creation of a pseudolumen that may compress the true aortic lumen. Predisposing factors mediate their risk by either increasing tension on the wall or by causing structural degeneration. They include hypertension, atherosclerosis, and a number of connective tissue diseases. If it goes undetected, aortic dissection carries a significant mortality risk; therefore, a high degree of clinical suspicion and a prompt diagnosis are required to maximize survival chances. Imaging methods, most commonly a CT scan, are essential for diagnosis; however, several studies have also investigated the effect of several biomarkers to aid in the detection of the condition. The choice of intervention varies depending on the type of dissection, with open surgical repair remaining of choice in those with type. In dissections, however, the role of conventional open surgery has considerably diminished in complicated type B dissections, with endovascular repair, a much less invasive technique, proving to be more effective. In uncomplicated type B dissections, where medical choice reigned supreme as the optimal intervention, endovascular repair is being explored as a viable option which may reduce long- term mortality outcomes, although the ideal intervention in this situation is far from settled.
10.2174/1573403X16666201014142930
Aortic dissection reconsidered: type, entry site, malperfusion classification adding clarity and enabling outcome prediction.
Sievers Hans-Hinrich,Rylski Bartosz,Czerny Martin,Baier Anna L M,Kreibich Maximilian,Siepe Matthias,Beyersdorf Friedhelm
Interactive cardiovascular and thoracic surgery
OBJECTIVES:Aortic dissection is complex. Imaging and treatment modalities are evolving, demanding a more differentiated but pragmatic dissection classification. Our goal was to provide a new practical classification system including Type of dissection, location of the tear of the primary Entry and Malperfusion (TEM). METHODS:We extended the Stanford dissection classification (A and B) by adding non-A non-B aortic dissection, the location of the primary entry tear (E) and malperfusion (M). A 0 was added if the primary entry tear was not visible; 1, if it was in the ascending aorta; 2, if it was in the arch; and 3, if it was in the descending aorta (E0, E1, E2, E3). We added 0 if malperfusion was absent; 1, if coronary arteries; 2, if supra-aortic vessels; and 3, if visceral/renal and/or a lower extremity was affected (M0, M1, M2, M3). Plus (+) was added if malperfusion was clinically present and minus (-) if it was a radiological finding. RESULTS:The new classification system was analysed in 357 patients retrospectively; distribution was 59%, 31% and 10% for A, B and non-A non-B dissections. The in-hospital mortality rate was 16%, 5% and 8% (P = 0.01). Postoperative stroke occurred in 14%, 1% and 3% (P < 0.001). The in-hospital mortality rate was 22%, 14%, 40% and 0% in A E0, E1, E2 and E3 (P = 0.023), respectively. Two years after the onset of dissection, the lowest survival rate was observed in A, followed by non-A non-B and B (83 ± 3% vs 88 ± 6% vs 93 ± 3%; P = 0.019). CONCLUSIONS:The new practical TEM aortic dissection classification system adds clarity regarding the extent of the disease process, enhances awareness of the disease mechanism, aids in decision-making regarding the extent of repair and helps in anticipating outcome.
10.1093/icvts/ivz281
Targeting endothelial tight junctions to predict and protect thoracic aortic aneurysm and dissection.
European heart journal
AIMS:Whether changes in endothelial tight junctions (TJs) lead to the formation of thoracic aortic aneurysm and dissection (TAAD) and serve as an early indicator and therapeutic target remains elusive. METHODS AND RESULTS:Single-cell RNA sequencing analysis showed aberrant endothelial TJ expressions in the thoracic aortas of patients with TAAD. In a β-aminopropionitrile (BAPN)-induced TAAD mouse model, endothelial TJ function was disrupted in the thoracic aortas at an early stage (5 and 10 days) as observed by a vascular permeability assay, while the intercellular distribution of crucial TJ components was significantly decreased by en face staining. For the non-invasive detection of endothelial TJ function, two dextrans of molecular weights 4 and 70 kDa were conjugated with the magnetic resonance imaging (MRI) contrast agent Gd-DOTA to synthesize FITC-dextran-DOTA-Gd and rhodamine B-dextran-DOTA-Gd. MRI images showed that both probes accumulated in the thoracic aortas of the BAPN-fed mice. Particularly, the mice with increased accumulated signals from 5 to 10 days developed TAAD at 14 days, whereas the mice with similar signals between the two time points did not. Furthermore, the protease-activated receptor 2 inhibitor AT-1001, which seals TJs, alleviated the BAPN-induced impairment of endothelial TJ function and expression and subsequently reduced TAAD incidence. Notably, endothelial-targeted ZO-1 conditional knockout increased TAAD incidence. Mechanistically, vascular inflammation and edema were observed in the thoracic aortas of the BAPN-fed mice, whereas these phenomena were attenuated by AT-1001. CONCLUSION:The disruption of endothelial TJ function is an early event prior to TAAD formation, herein serving as a potential indicator and a promising target for TAAD.
10.1093/eurheartj/ehac823
Acute aortic dissection.
Lancet (London, England)
Although substantial progress has been made in the prevention, diagnosis, and treatment of acute aortic dissection, it remains a complex cardiovascular event, with a high immediate mortality and substantial morbidity in individuals surviving the acute period. The past decade has allowed a leap forward in understanding the pathophysiology of this disease; the existing classifications have been challenged, and the scientific community moves towards a nomenclature that is likely to unify the current definitions according to morphology and function. The most important pathophysiological pathway, namely the location and extension of the initial intimal tear, which causes a disruption of the media layer of the aortic wall, together with the size of the affected aortic segments, determines whether the patient should undergo emergency surgery, an endovascular intervention, or receive optimal medical treatment. The scientific evidence for the management and follow-up of acute aortic dissection continues to evolve. This Seminar provides a clinically relevant overview of potential prevention, diagnosis, and management of acute aortic dissection, which is the most severe acute aortic syndrome.
10.1016/S0140-6736(22)01970-5
Acute aortic dissection: evidence, uncertainties, and future therapies.
European heart journal
Remarkable progress has become especially apparent in aortic medicine in the last few decades, leading to essential changes in how thoracic aortic dissection is understood and treated. This state-of-the-art review article addresses the mechanisms of acute aortic dissection, explaining the role of its primary entry location, proximal, and distal dissection extension in their clinical presentation and impact on the decision-making process towards the best treatment approach. The latest evidence on novel treatment methods for acute aortic syndromes is presented, and the diverse dissection classification systems that remain uncertain are discussed, which reveals the need for shared terminology and more clarity. Finally, future aspects are discussed in treating acute aortic dissection, such as the endovascular treatment of aortic dissection Type A and biomarkers for acute aortic syndromes.
10.1093/eurheartj/ehac757
The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease.
Hagan P G,Nienaber C A,Isselbacher E M,Bruckman D,Karavite D J,Russman P L,Evangelista A,Fattori R,Suzuki T,Oh J K,Moore A G,Malouf J F,Pape L A,Gaca C,Sechtem U,Lenferink S,Deutsch H J,Diedrichs H,Marcos y Robles J,Llovet A,Gilon D,Das S K,Armstrong W F,Deeb G M,Eagle K A
JAMA
CONTEXT:Acute aortic dissection is a life-threatening medical emergency associated with high rates of morbidity and mortality. Data are limited regarding the effect of recent imaging and therapeutic advances on patient care and outcomes in this setting. OBJECTIVE:To assess the presentation, management, and outcomes of acute aortic dissection. DESIGN:Case series with patients enrolled between January 1996 and December 1998. Data were collected at presentation and by physician review of hospital records. SETTING:The International Registry of Acute Aortic Dissection, consisting of 12 international referral centers. PARTICIPANTS:A total of 464 patients (mean age, 63 years; 65.3% male), 62.3% of whom had type A dissection. MAIN OUTCOME MEASURES:Presenting history, physical findings, management, and mortality, as assessed by history and physician review of hospital records. RESULTS:While sudden onset of severe sharp pain was the single most common presenting complaint, the clinical presentation was diverse. Classic physical findings such as aortic regurgitation and pulse deficit were noted in only 31.6% and 15.1% of patients, respectively, and initial chest radiograph and electrocardiogram were frequently not helpful (no abnormalities were noted in 12.4% and 31.3% of patients, respectively). Computed tomography was the initial imaging modality used in 61.1%. Overall in-hospital mortality was 27.4%. Mortality of patients with type A dissection managed surgically was 26%; among those not receiving surgery (typically because of advanced age and comorbidity), mortality was 58%. Mortality of patients with type B dissection treated medically was 10.7%. Surgery was performed in 20% of patients with type B dissection; mortality in this group was 31.4%. CONCLUSIONS:Acute aortic dissection presents with a wide range of manifestations, and classic findings are often absent. A high clinical index of suspicion is necessary. Despite recent advances, in-hospital mortality rates remain high. Our data support the need for continued improvement in prevention, diagnosis, and management of acute aortic dissection.
10.1001/jama.283.7.897
Research Progress on the Pathogenesis of Aortic Aneurysm and Dissection in Metabolism.
Current problems in cardiology
Aortic aneurysm and dissection are complicated diseases having both high prevalence and mortality. It is usually diagnosed at advanced stages and posing diagnostic and therapeutic challenges due to the limitations of current detecting methods for aortic dissection used in clinics. Metabonomics demonstrated its great potential capability in the early diagnosis and personalized treatment of several diseases. Emerging evidence suggests that metabolic disorders including amino acid metabolism, glycometabolism, and lipid metabolism disturbance are involved in the pathogenesis of aortic aneurysm and dissection by affecting multiple functional aortic cells. The purpose of this review is to provide new insights into the metabolism alterations and their related regulatory mechanisms with a focus on recent advances and findings and provide a theoretical basis for the diagnosis, prevention, and drug development for aortic aneurysm and dissection.
10.1016/j.cpcardiol.2023.102040
Transcriptome analysis reveals therapeutic potential of NAMPT in protecting against abdominal aortic aneurysm in human and mouse.
Bioactive materials
Abdominal Aortic Aneurysm (AAA) is a life-threatening vascular disease characterized by the weakening and ballooning of the abdominal aorta, which has no effective therapeutic approaches due to unclear molecular mechanisms. Using single-cell RNA sequencing, we analyzed the molecular profile of individual cells within control and AAA abdominal aortas. We found cellular heterogeneity, with increased plasmacytoid dendritic cells and reduced endothelial cells and vascular smooth muscle cells (VSMCs) in AAA. Up-regulated genes in AAA were associated with muscle tissue development and apoptosis. Genes controlling VSMCs aberrant switch from contractile to synthetic phenotype were significantly enriched in AAA. Additionally, VSMCs in AAA exhibited cell senescence and impaired oxidative phosphorylation. Similar observations were made in a mouse model of AAA induced by Angiotensin II, further affirming the relevance of our findings to human AAA. The concurrence of gene expression changes between human and mouse highlighted the impairment of oxidative phosphorylation as a potential target for intervention. Nicotinamide phosphoribosyltransferase (NAMPT, also named VISFATIN) signaling emerged as a signature event in AAA. NAMPT was significantly downregulated in AAA. NAMPT-extracellular vesicles (EVs) derived from mesenchymal stem cells restored NAMPT levels, and offered protection against AAA. Furthermore, NAMPT-EVs not only repressed injuries, such as cell senescence and DNA damage, but also rescued impairments of oxidative phosphorylation in both mouse and human AAA models, suggesting NAMPT supplementation as a potential therapeutic approach for AAA treatment. These findings shed light on the cellular heterogeneity and injuries in AAA, and offered promising therapeutic intervention for AAA treatment.
10.1016/j.bioactmat.2023.11.020
Applications of Extracellular Vesicles in Abdominal Aortic Aneurysm.
Frontiers in cardiovascular medicine
Abdominal aortic aneurysm (AAA) is a localized expansion of the abdominal aorta which can lead to lethal complication as the rupture of aortic wall. Currently there is still neither competent method to predict the impending rupture of aneurysm, nor effective treatment to arrest the progression of small and asymptomatic aneurysms. Accumulating evidence has confirmed the crucial role of extracellular vesicles (EVs) in the pathological course of AAA, acting as important mediators of intercellular communication. Given the advantages of intrinsic targeting properties, lower toxicity and fair stability, EVs show great potential to serve as biomarkers, therapeutic agents and drug delivery carriers. However, EV therapies still face several major challenges before they can be applied clinically, including off-target effect, low accumulation rate and rapid clearance by mononuclear phagocyte system. In this review, we first illustrate the roles of EV in the pathological process of AAA and evaluate its possible clinical applications. We also identify present challenges for EV applications, highlight different strategies of EV engineering and constructions of EV-like nanoparticles, including EV display technology and membrane hybrid technology. These leading-edge techniques have been recently employed in multiple cardiovascular diseases and their promising application in the field of AAA is discussed.
10.3389/fcvm.2022.927542
Circulating small extracellular vesicles promote proliferation and migration of vascular smooth muscle cells via AXL and MerTK activation.
Acta pharmacologica Sinica
The proliferation and migration of vascular smooth muscle cells (VSMCs) after vascular injury lead to neointimal hyperplasia, thus aggravating vascular diseases. However, the molecular mechanisms underlying neointima formation are not fully elucidated. Extracellular vesicles (EVs) are mediators of various intercellular communications. The potential of EVs as regulators in cardiovascular diseases has raised significant interest. In the current study we investigated the role of circulating small extracellular vesicles (csEVs), the most abundant EVs (10 EVs/mL serum) in VSMC functions. csEVs were prepared from bovine, porcine or rat serum. We showed that incubation with csEVs (0.5 × 10-2 × 10) dose-dependently enhanced the proliferation and migration of VSMCs via the membrane phosphatidylserine (PS). In rats with ligation of right carotid artery, we demonstrated that application of csEVs in the ligated vessels aggravated neointima formation via interaction of membrane PS with injury. Furthermore, incubation with csEVs markedly enhanced the phosphorylation of AXL and MerTK in VSMCs. Pretreatment with BSM777607 (pan-TAM inhibitor), bemcentinib (AXL inhibitor) or UNC2250 (MerTK inhibitor) blocked csEV-induced proliferation and migration of VSMCs. We revealed that csEV-activated AXL and MerTK shared the downstream signaling pathways of Akt, extracellular signal-regulated kinase (ERK) and focal adhesion kinase (FAK) that mediated the effects of csEVs. We also found that csEVs increased the expression of AXL through activation of transcription factor YAP, which might constitute an AXL-positive feedback loop to amplify the signals. Finally, we demonstrated that dual inhibition of AXL/MerTK by ONO-7475 (0.1 µM) effectively hindered csEV-mediated proliferation and migration of VSMCs in ex vivo mouse aorta injury model. Based on these results, we propose an essential role for csEVs in proliferation and migration of VSMCs and highlight the feasibility of dual AXL/MerTK inhibitors in the treatment of vascular diseases.
10.1038/s41401-022-01029-8
Role of Extracellular Vesicles as Potential Diagnostic and/or Therapeutic Biomarkers in Chronic Cardiovascular Diseases.
Martin-Ventura Jose Luis,Roncal Carmen,Orbe Josune,Blanco-Colio Luis Miguel
Frontiers in cell and developmental biology
Cardiovascular diseases (CVDs) are the first cause of death worldwide. In recent years, there has been great interest in the analysis of extracellular vesicles (EVs), including exosomes and microparticles, as potential mediators of biological communication between circulating cells/plasma and cells of the vasculature. Besides their activity as biological effectors, EVs have been also investigated as circulating/systemic biomarkers in different acute and chronic CVDs. In this review, the role of EVs as potential diagnostic and prognostic biomarkers in chronic cardiovascular diseases, including atherosclerosis (mainly, peripheral arterial disease, PAD), aortic stenosis (AS) and aortic aneurysms (AAs), will be described. Mechanistically, we will analyze the implication of EVs in pathological processes associated to cardiovascular remodeling, with special emphasis in their role in vascular and valvular calcification. Specifically, we will focus on the participation of EVs in calcium accumulation in the pathological vascular wall and aortic valves, involving the phenotypic change of vascular smooth muscle cells (SMCs) or valvular interstitial cells (IC) to osteoblast-like cells. The knowledge of the implication of EVs in the pathogenic mechanisms of cardiovascular remodeling is still to be completely deciphered but there are promising results supporting their potential translational application to the diagnosis and therapy of different CVDs.
10.3389/fcell.2022.813885
Differential expression profile of plasma exosomal microRNAs in acute type A aortic dissection with acute lung injury.
Scientific reports
MicroRNAs (miRNAs) packaged into exosomes mediate cell communication and contribute to the pathogenesis of acute type A aortic dissection (ATAAD) with acute lung injury (ALI). The expression profile of plasma exosomal miRNAs in ATAAD patients with ALI hasn't been identified. We performed a miRNA-sequencing to analyze the differentially expressed miRNAs (DE-miRNAs) of circulating exosomes in ATAAD patients with ALI compared to patients without ALI, founding 283 specific miRNAs in two groups. We respectively selected the top 10 downregulated and upregulated DE-miRNAs for further studies. The predicted transcription factors (TFs) of these DE-miRNAs were SMAD2, SRSF1, USF1, etc. The Gene Ontology (GO) and Kyoto Encyclopedia Genes and Genomes (KEGG) analysis predicted their target genes mainly involved acute inflammatory response, cell junction, cytoskeleton, NF-κB signaling pathway, etc. Construction and analysis of the PPI network revealed that RHOA and INSR were considered hub genes with the highest connectivity degrees. Moreover, we confirmed two exosomal miRNAs (hsa-miR-485-5p and hsa-miR-206) by real-time quantitative polymerase chain reaction (RT-qPCR) in a validation cohort. Our study identified a plasma exosomal miRNAs signature related to ATAAD with ALI. Certain DE-miRNAs may contribute to the progression of this disease, which help us better understand the pathogenesis of ATAAD with ALI.
10.1038/s41598-022-15859-3
Telocytes in the human ascending aorta: Characterization and exosome-related KLF-4/VEGF-A expression.
Aschacher Thomas,Schmidt Katy,Aschacher Olivia,Eichmair Eva,Baranyi Ulrike,Winkler Bernhard,Grabenwoeger Martin,Spittler Andreas,Enzmann Florian,Messner Barbara,Riebandt Julia,Laufer Guenther,Bergmann Michael,Ehrlich Marek
Journal of cellular and molecular medicine
Telocytes (TCs), a novel interstitial cell entity promoting tissue regeneration, have been described in various tissues. Their role in inter-cellular signalling and tissue remodelling has been reported in almost all human tissues. This study hypothesizes that TC also contributes to tissue remodelling and regeneration of the human thoracic aorta (HTA). The understanding of tissue homeostasis and regenerative potential of the HTA is of high clinical interest as it plays a crucial role in pathogenesis from aortic dilatation to lethal dissection. Therefore, we obtained twenty-five aortic specimens of heart donors during transplantation. The presence of TCs was detected in different layers of aortic tissue and characterized by immunofluorescence and transmission electron microscopy. Further, we cultivated and isolated TCs in highly differentiated form identified by positive staining for CD34 and c-kit. Aortic-derived TC was characterized by the expression of PDGFR-α, PDGFR-β, CD29/integrin β-1 and αSMA and the stem cell markers Nanog and KLF-4. Moreover, TC exosomes were isolated and characterized for soluble angiogenic factors by Western blot. CD34 /c-kit TCs shed exosomes containing the soluble factors VEGF-A, KLF-4 and PDGF-A. In summary, TC occurs in the aortic wall. Correspondingly, exosomes, derived from aortic TCs, contain vasculogenesis-relevant proteins. Understanding the regulation of TC-mediated aortic remodelling may be a crucial step towards designing strategies to promote aortic repair and prevent adverse remodelling.
10.1111/jcmm.16919
Circulating exosomal miRNAs as novel biomarkers for acute aortic dissection: A diagnostic accuracy study.
Medicine
BACKGROUND:Acute aortic dissection (AAD) is a serious and life-threatening cardiovascular emergency. This study aim to investigate whether MicroRNAs (miRNAs)in circulating exosomes could serve as novel diagnostic biomarkers for AAD. METHODS:Using miRNA microarray sequencing, the differentially expressed exosomal miRNAs between AAD patients and control subjects were found. In this study, we investigated 8 miRNAs (miR-499a-5p/miR-543/miR-143-3p/miR-4433b-3p/miR-744-5p/miR-4488/miR-202-3p/miR-206), 4 Proteins (Matrix Metalloprotein-9/12)/transforming growth factor-β/D-Dimer) in AAD (n = 75) and Control (n = 86) expression levels between the 2 groups. The combined diagnostic of exosomal miRNAs and Proteins was performed (area under curve [AUC] > 0.8, R > 0.5 and P < .01). The Receiver Operating Characteristic curve was drawn to evaluate the diagnostic efficacy. Predict the gene targets of differentially expressed miRNAs and analyze the functions and signaling pathways of these targets using online databases. RESULTS:The exosomes isolated from the 2 groups of serum were bilayer membranes with a diameter of about 100 nm. Stably expressed in CD9, CD63 and TSG101. Compared with the control subjects, 8 exosomal miRNAs (miR-499a-5p, miR-543, miR-206, miR-143-3p, miR-4433b-3p, miR-744-5p, miR- 4488, and miR-202-3p) were regulated to varying degrees (P < .05). miR-499a-5p, miR-202-3p, and D-Dimer had higher diagnostic efficacy (AUC > 0.90). Among them, miR-499a-5p had the highest diagnostic accuracy, reaching 95%, AUC = 0.99. Co-diagnosis of positively correlated miRNAs and Proteins improves the diagnostic performance. The combined diagnostic accuracy of miR-499a-5p and miR-202-3p was 98% (AUC = 0.998), and the sensitivity and specificity were 98%. The combined diagnostic accuracy of miR-499a-5p and matrix metalloprotein-9 was 98% (AUC = 0.996), and the sensitivity and specificity were 98%. Gene Ontology (GO) enrichment analysis and Kyoto encyclopedia of genes and genomes signaling pathway analysis, some predicted targets of these miRNAs are involved in the pathophysiological process of AAD. CONCLUSION:Serum exosomal miR-499a-5p, miR-143-3p, and miR-202-3p can be used as potential diagnostic biomarkers for AAD, and the combination of various markers can coordinate and complement each other, and can significantly improve the diagnosis of aortic dissection sensitivity and specificity.
10.1097/MD.0000000000034474
ER stress dependent microparticles derived from smooth muscle cells promote endothelial dysfunction during thoracic aortic aneurysm and dissection.
Jia Li-Xin,Zhang Wen-Mei,Li Tao-Tao,Liu Yan,Piao Chun-Mei,Ma You-Cai,Lu Yu,Wang Yuan,Liu Ting-Ting,Qi Yong-Fen,Du Jie
Clinical science (London, England : 1979)
The degeneration of vascular smooth muscle cell(s) (SMC) is one of the key features of thoracic aortic aneurysm and dissection (TAAD). We and others have shown that elevated endoplasmic reticulum (ER) stress causes SMC loss and TAAD formation, however, the mechanism of how SMC dysfunction contributes to intimal damage, leading to TAAD, remains to be explored. In the present study, assay demonstrated that elevated mechanical stretch (18% elongation, 3600 cycles/h) stimulated the ER stress response and microparticle(s) (MP) production from both SMC and endothelial cell(s) (EC) in a time-dependent manner. Treatment of EC with isolated MP led to anoikis, which was determined by measuring the fluorescence of the ethidium homodimer (EthD-1) and Calcein AM cultured in hydrogel-coated plates and control plates. MP stimulation of EC also up-regulated the mRNA levels of inflammatory molecules (i.e. Vascular cellular adhesion molecular-1 (VCAM-1)), intercellular adhesion molecular-1 (ICAM-1), interleukin-1β (IL-1β), and interleukin-6 (IL-6)). Use of an ER stress inhibitor or knockout of CHOP decreased mechanical stretch-induced MP production in SMC. , administration of an ER stress inhibitor or knockout of CHOP suppressed both apoptosis of EC and the infiltration of inflammatory cells. Moreover, TAAD formation was also suppressed by the administration of an ER stress inhibitor. In conclusion, our study demonstrates that elevated mechanical stretch induces MP formation in SMC leading to endothelial dysfunction, which is ER stress dependent. The inhibition of ER stress suppressed EC apoptosis, inflammation in the aorta, and TAAD development.
10.1042/CS20170252
CXCR6 Mediates Pressure Overload-Induced Aortic Stiffness by Increasing Macrophage Recruitment and Reducing Exosome-miRNA29b.
Journal of cardiovascular translational research
Aortic stiffness is an independent risk factor for aortic diseases such as aortic dissection which commonly occurred with aging and hypertension. Chemokine receptor CXCR6 is critically involved in vascular inflammation and remodeling. Here, we investigated whether and how CXCR6 plays a role in aortic stiffness caused by pressure overload. CXCR6 and WT mice underwent transverse aortic constriction (TAC) surgery for 8 weeks. CXCR6 deficiency significantly improved TAC-induced aortic remodeling and endothelial dysfunction by decreasing CD11c macrophage infiltration, suppressing VCAM-1 and ICAM-1, reducing collagen deposition, and downregulating MMP12 and osteopontin in the aorta. Consistently, blocking the CXCL16/CXCR6 axis also reduced aortic accumulation of CD11c macrophages and vascular stiffness but without affecting the release of TNF-α and IL-6 from the aorta. Furthermore, pressure overload inhibited aortic release of exosomes, which could be reversed by suppressing CXCR6 or CXCL16. Inhibition of exosome release by GW4869 significantly aggravated TAC-induced aortic calcification and stiffness. By exosomal microRNA microarray analysis, we found that microRNA-29b was significantly reduced in aortic endothelial cells (AECs) receiving TAC. Intriguingly, blocking the CXCL16/CXCR6 axis restored the expression of miR-29b in AECs. Finally, overexpression of miR-29b significantly increased eNOS and reduced MMPs and collagen in AECs. By contrast, antagonizing miR-29b in vivo further enhanced TAC-induced expressions of MMP12 and osteopontin, aggravated aortic fibrosis, calcification, and stiffness. Our study demonstrated a key role of the CXCL16/CXCR6 axis in macrophage recruitment and macrophage-mediated aortic stiffness under pressure overload through an exosome-miRNAs-dependent manner.
10.1007/s12265-022-10304-2
Oral Piwi-Interacting RNA Delivery Mediated by Green Tea-Derived Exosome-Like Nanovesicles for the Treatment of Aortic Dissection.
Advanced healthcare materials
Aortic dissection (AD) is a severe cardiovascular disease necessitating active therapeutic strategies for early intervention and prevention. Nucleic acid drugs, known for their potent molecule-targeting therapeutic properties, offer potential for genetic suppression of AD. Piwi-interacting RNAs, a class of small RNAs, hold promise for managing cardiovascular diseases. Limited research on these RNAs and AD exists. This study demonstrates that an antagomir targeting heart-apoptosis-associated piRNA (HAAPIR) effectively regulates vascular remodeling, mitigating AD occurrence and progression through the myocyte enhancer factor 2D (Mef2D) and matrix metallopeptidase 9 (MMP9) pathways. Green tea-derived plant exosome-like nanovesicles (PELNs) are used for oral administration of antagomir. The antagomir-HAAPIR-nanovesicle complex, after purification and optimization, exhibits a high packing rate, while the antagomir is resistant to enzyme digestion. Administered to mice, the complex targets the aortic lesion, reducing AD incidence and improving survival. Moreover, MMP9 and Mef2D expression decrease significantly, inhibiting the phenotypic conversion of human aortic smooth muscle cells. PELNs encapsulate the antagomir-HAAPIR complex, maintaining stability, mediating transport into the bloodstream, and delivering Piwi-interacting RNAs to AD sites. Thus, HAAPIR is a potential target for persistent clinical AD prevention and treatment, and nanovesicle-encapsulated nucleic acids offer a promising cardiovascular disease treatment, providing insights for other therapeutic targets.
10.1002/adhm.202401466
3D-printing hydrogel programmed released exosomes to restore aortic medial degeneration through inhibiting VSMC ferroptosis in aortic dissection.
Journal of nanobiotechnology
Aortic dissection (AD) is a devastating disease with a high mortality rate. Exosomes derived from mesenchymal stem cells (exo-MSCs) offer a promising strategy to restore aortic medial degeneration and combat ferroptosis in AD. However, their rapid degradation in the circulatory system and low treatment efficiency limit their clinical application. Methylacrylated gelatin (Gelma) was reported as a matrix material to achieve controlled release of exosomes. Herein, exo-MSCs-embedded in Gelma hydrogels (Gelma-exos) using ultraviolet light and three-dimensional (3D) printing technology. These Gelma-exos provide a sustained release of exo-MSCs as Gelma gradually degrades, helping to restore aortic medial degeneration and prevent ferroptosis. The sustained release of exosomes can inhibit the phenotypic switch of vascular smooth muscle cells (VSMCs) to a proliferative state, and curb their proliferation and migration. Additionally, the 3D-printed Gelma-exos demonstrated the ability to inhibit ferroptosis in vitro, in vivo and ex vivo experiments. In conclusion, our Gelma-exos, combined with 3D-printed technology, offer an alternative treatment approach for repairing aortic medial degeneration and ferroptosis in AD, potentially reducing the incidence of aortic dissection rupture.
10.1186/s12951-024-02821-w
MiR-574-5p: A Circulating Marker of Thoracic Aortic Aneurysm.
Boileau Adeline,Lino Cardenas Christian L,Courtois Audrey,Zhang Lu,Rodosthenous Rodosthenis S,Das Saumya,Sakalihasan Natzi,Michel Jean-Baptiste,Lindsay Mark E,Devaux Yvan
International journal of molecular sciences
Thoracic aortic aneurysm (TAA) can lead to fatal complications such as aortic dissection. Since aneurysm dimension poorly predicts dissection risk, microRNAs (miRNAs) may be useful to diagnose or risk stratify TAA patients. We aim to identify miRNAs associated with TAA pathogenesis and that are possibly able to improve TAA diagnosis. MiRNA microarray experiments of aortic media tissue samples from 19 TAA patients and 19 controls allowed identifying 232 differentially expressed miRNAs. Using interaction networks between these miRNAs and 690 genes associated with TAA, we identified miR-574-5p as a potential contributor of TAA pathogenesis. Interestingly, miR-574-5p was significantly down-regulated in the TAA tissue compared to the controls, but was up-regulated in serum samples from a separate group of 28 TAA patients compared to 20 controls ( < 0.001). MiR-574-5p serum levels discriminated TAA patients from controls with an area under the receiver operating characteristic curve of 0.87. In the mouse model, miR-574-5p was down-regulated in aortic tissue compared to wild-type ( < 0.05), and up-regulated in plasma extracellular vesicles from mice compared to wild-type mice ( < 0.05). Furthermore, in vascular smooth muscle cells, angiotensin II appears to induce miR-574-5p secretion in extracellular vesicles. In conclusion, miR-574-5p is associated with TAA pathogenesis and may help in diagnosing this disease.
10.3390/ijms20163924
Analysis of Extracellular Vesicle-Mediated Vascular Calcification Using In Vitro and In Vivo Models.
Journal of visualized experiments : JoVE
Cardiovascular disease is the leading cause of death in the world, and vascular calcification is the most significant predictor of cardiovascular events; however, there are currently no treatment or therapeutic options for vascular calcification. Calcification begins within specialized extracellular vesicles (EVs), which serve as nucleating foci by aggregating calcium and phosphate ions. This protocol describes methods for obtaining and assessing calcification in murine aortas and analyzing the associated extracted EVs. First, gross dissection of the mouse is performed to collect any relevant organs, such as the kidneys, liver, and lungs. Then, the murine aorta is isolated and excised from the aortic root to the femoral artery. Two to three aortas are then pooled and incubated in a digestive solution before undergoing ultracentrifugation to isolate the EVs of interest. Next, the mineralization potential of the EVs is determined through incubation in a high-phosphate solution and measuring the light absorbance at a wavelength of 340 nm. Finally, collagen hydrogels are used to observe the calcified mineral formation and maturation produced by the EVs in vitro.
10.3791/65013
The Role of Telocytes and Telocyte-Derived Exosomes in the Development of Thoracic Aortic Aneurysm.
International journal of molecular sciences
A hallmark of thoracic aortic aneurysms (TAA) is the degenerative remodeling of aortic wall, which leads to progressive aortic dilatation and resulting in an increased risk for aortic dissection or rupture. Telocytes (TCs), a distinct type of interstitial cells described in many tissues and organs, were recently observed in the aortic wall, and studies showed the potential regulation of smooth muscle cell (SMC) homeostasis by TC-released shed vesicles. The purpose of the present work was to study the functions of TCs in medial degeneration of TAA. During aneurysmal formation an increase of aortic TCs was identified in human surgical specimens of TAA-patients, compared to healthy thoracic aortic (HTA)-tissue. We found the presence of epithelial progenitor cells in the adventitial layer, which showed increased infiltration in TAA samples. For functional analysis, HTA- and TAA-telocytes were isolated, characterized, and compared by their protein levels, mRNA- and miRNA-expression profiles. We detected TC and TC-released exosomes near SMCs. TAA-TC-exosomes showed a significant increase of the SMC-related dedifferentiation markers KLF-4-, VEGF-A-, and PDGF-A-protein levels, as well as miRNA-expression levels of miR-146a, miR-221 and miR-222. SMCs treated with TAA-TC-exosomes developed a dedifferentiation-phenotype. In conclusion, the study shows for the first time that TCs are involved in development of TAA and could play a crucial role in SMC phenotype switching by release of extracellular vesicles.
10.3390/ijms23094730
The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy.
Oduro Patrick Kwabena,Zheng Xianxian,Wei Jinna,Yang Yanze,Wang Yuefei,Zhang Han,Liu Erwei,Gao Xiumei,Du Mei,Wang Qilong
Acta pharmaceutica Sinica. B
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS-STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure, myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns (mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS-STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism. Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS-STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases.
10.1016/j.apsb.2021.05.011