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The aorta is the ‘greatest artery’, through which oxygenated blood is delivered from the left ventricle to end organs with each cardiac cycle (200 million litres of blood transported in an average lifetime). The aorta can be affected by a wide spectrum of acute factors (such as cocaine use, weight lifting and trauma) and chronic acquired and/or genetic conditions (such as systemic arterial hypertension and phaeochromocytoma), which variously lead to increased aortic wall stress. The medial layer of the aorta can also be subject to abnormalities (such as Marfan syndrome, bicuspid aortic valve, inflammatory vasculitis, atherosclerosis and infections). Despite important advances in diagnostic and therapeutic interventions, data derived from registries and population-based studies highlight that the burden of aortic diseases remains high. Therefore, specific resources need to be allocated to design and implement preventive strategies (healthy lifestyles, modifications to cardiovascular risk factors, and educational and screening programmes) at individual and community levels. In this Review, we discuss the epidemiology, management and outcomes of the most common aortic diseases, namely, aortic aneurysms and acute aortic syndromes.In this Review, Bossone and Eagle discuss the epidemiology, management and outcomes of the most common aortic diseases: aortic aneurysms and acute aortic syndromes, including aortic dissection.

Aortic aneurysm is a chronic disease characterized by localized expansion of the aorta, including the ascending aorta, arch, descending aorta, and abdominal aorta. Although aortic aneurysms are generally asymptomatic, they can threaten human health by sudden death due to aortic rupture. Aortic aneurysms are estimated to lead to 150,000 ~ 200,000 deaths per year worldwide. Currently, there are no effective drugs to prevent the growth or rupture of aortic aneurysms; surgical repair or endovascular repair is the only option for treating this condition. The pathogenic mechanisms and therapeutic targets for aortic aneurysms have been examined over the past decade; however, there are unknown pathogenic mechanisms involved in cellular heterogeneity and plasticity, the complexity of the transforming growth factor-β signaling pathway, inflammation, cell death, intramural neovascularization, and intercellular communication. This review summarizes the latest research findings and current pathogenic mechanisms of aortic aneurysms, which may enhance our understanding of aortic aneurysms. New Insights into Complex Pathologies of Aortic Aneurysms Aortic aneurysms, a chronic aortic disease, can lead to life-threatening consequences. Recent advancements in understanding the pathophysiological mechanisms of aortic aneurysms have focused on the source of therapeutic targets. The heterogeneity of aortic cells during the progress of an aortic aneurysm is augmented by the alteration of gene expression that changes the phenotype and function of the aortic cells. Inflammatory cells, cytokines production, matrix metalloproteinases, smooth muscle cells phenotypic switching, SMCs death, neovascularization, and thrombosis contribute to the development and progression of aortic aneurysms. Neutralization of transforming growth factor-β in mouse aortic aneurysm models exhibits different consequences in the progress of aortic aneurysms depending on experimental designs. Extracellular vesicles contain various contents with biological activity and are released from donor cells to target cells or organs, potentially promoting or preventing the progress of aortic aneurysms. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Abdominal aortic aneurysm has a high heritability and often co-occurs with other cardiometabolic disorders, suggesting shared genetic susceptibility. We investigate this commonality leveraging recent GWAS studies of abdominal aortic aneurysm and 32 cardiometabolic traits. We find significant genetic correlations between abdominal aortic aneurysm and 21 of the cardiometabolic traits investigated, including causal relationships with coronary artery disease, hypertension, lipid traits, and blood pressure. For each trait pair, we identify shared causal variants, genes, and pathways, revealing that cholesterol metabolism and inflammation are shared most prominently. Additionally, we show the tissue and cell type specificity in the shared signals, with strong enrichment across traits in the liver, arteries, adipose tissues, macrophages, adipocytes, and fibroblasts. Finally, we leverage drug-gene databases to identify several lipid-lowering drugs and antioxidants with high potential to treat abdominal aortic aneurysm with comorbidities. Our study provides insight into the shared genetic mechanism between abdominal aortic aneurysm and cardiometabolic traits, and identifies potential targets for pharmacological intervention. Here, the authors identify SNPs, genes, pathways, cells and tissues shared between abdominal aortic aneurysm and 21 cardiometabolic traits, generating a reference for common mechanisms and identifying drugs for comorbid conditions.

Mechanical overload of the vascular wall is a pathological hallmark of life-threatening abdominal aortic aneurysms (AAA). However, how this mechanical stress resonates at the unicellular level of vascular smooth muscle cells (VSMC) is undefined. Here we show defective mechano-phenotype signatures of VSMC in AAA measured with ultrasound tweezers-based micromechanical system and single-cell RNA sequencing technique. Theoretical modelling predicts that cytoskeleton alterations fuel cell membrane tension of VSMC, thereby modulating their mechanoallostatic responses which are validated by live micromechanical measurements. Mechanistically, VSMC gradually adopt a mechanically solid-like state by upregulating cytoskeleton crosslinker, α-actinin2, in the presence of AAA-promoting signal, Netrin-1, thereby directly powering the activity of mechanosensory ion channel Piezo1. Inhibition of Piezo1 prevents mice from developing AAA by alleviating pathological vascular remodeling. Our findings demonstrate that deviations of mechanosensation behaviors of VSMC is detrimental for AAA and identifies Piezo1 as a novel culprit of mechanically fatigued aorta in AAA. Mechanobiological signals have been reported to contribute to abdominal aortic aneurysm (AAA) development. Here the authors report that the microskeletal stiffness and a Piezo1-mediated mechanism influence vascular smooth muscle cell mechanosensation and AAA disease development.

Neutrophil extracellular traps (NETs) play an important role in abdominal aortic aneurysm (AAA) formation; however, the underlying molecular mechanisms remain unclear. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) may exert therapeutic effects on AAA through their immunomodulatory and regenerative abilities. This study aimed to examine the role and mechanism of MSC-EVs in regulating the development of NET-mediated AAA. Excessive release of NETs was observed in patients with AAA, and the levels of NET components were associated with the clinical outcomes of the patients. Datasets from the Gene Expression Omnibus database were analyzed and revealed that the PI3K/AKT pathway and ferroptosis were strongly associated with NETosis during AAA formation. Further experiments verified that NETs promoted AAA formation by inducing ferroptosis in smooth muscle cells (SMCs) by inhibiting the PI3K/AKT pathway. The PI3K agonist 740 Y-P, the ferroptosis inhibitor ferrostatin-1, and Padi4 deficiency significantly prevented AAA formation. MSC-EVs attenuated AAA formation by reducing NET release in an angiotensin II-induced AAA mouse model. In vitro experiments revealed that MSC-EVs reduced the release of NETs by shifting NETosis to apoptosis. Our study indicates an important role for NET-induced SMC ferroptosis in AAA formation and provides several potential targets for AAA treatment. Vascular disease: Stem cell packets help reduce artery bulge Tiny membrane-bound packets of biomolecules secreted by stem cells in the bone marrow umbilical cord can reduce the development of dangerous bulges or ballooning in the aorta, the body’s largest artery. Liang Chen of China’s Shanghai Jiao Tong University School of Medicine and colleagues report that these stem cell-derived vesicles help to prevent such bulges, known as aneurysms, in mice through their effects on a type of immune cell called neutrophils, which release networks of DNA and protein at sites of inflammation. The neutrophil-produced molecules induced a type of cell death in the smooth muscle cells of the arterial wall, but the stem cell-secreted vesicles helped to suppress this process. These findings could lead to new therapies for people suffering from aortic aneurysm, a condition that can lead to life-threatening ruptures if left untreated.

Reprogramming of vascular smooth muscle cell (VSMC) differentiation plays an essential role in abdominal aortic aneurysm (AAA). However, the underlying mechanisms are still unclear. We explore the expression of FAM3A, a newly identified metabolic cytokine, and whether and how FAM3A regulates VSMC differentiation in AAA. We discover that FAM3A is decreased in the aortas and plasma in AAA patients and murine models. Overexpression or supplementation of FAM3A significantly attenuate the AAA formation, manifested by maintenance of the well-differentiated VSMC status and inhibition of VSMC transformation toward macrophage-, chondrocyte-, osteogenic-, mesenchymal-, and fibroblast-like cell subpopulations. Importantly, FAM3A induces KLF4 ubiquitination and reduces its phosphorylation and nuclear localization. Here, we report FAM3A as a VSMC fate-shaping regulator in AAA and reveal the underlying mechanism associated with KLF4 ubiquitination and stability, which may lead to the development of strategies based on FAM3A to restore VSMC homeostasis in AAA. The mechanisms underlying vascular smooth muscle cell reprogramming in abdominal aortic aneurism (AAA) remain unclear. Here they show that FAM3A, a metabolic cytokine, serves as a cell fate-shaping regulator of smooth muscle cells to protect against AAA formation.

An abdominal aortic aneurysm (AAA) is a localized dilatation of the infrarenal aorta. AAA is a multifactorial disease, and genetic and environmental factors play a part; smoking, male sex and a positive family history are the most important risk factors, and AAA is most common in men >65 years of age. AAA results from changes in the aortic wall structure, including thinning of the media and adventitia due to the loss of vascular smooth muscle cells and degradation of the extracellular matrix. If the mechanical stress of the blood pressure acting on the wall exceeds the wall strength, the AAA ruptures, causing life-threatening intra-abdominal haemorrhage — the mortality for patients with ruptured AAA is 65–85%. Although AAAs of any size can rupture, the risk of rupture increases with diameter. Intact AAAs are typically asymptomatic, and in settings where screening programmes with ultrasonography are not implemented, most cases are diagnosed incidentally. Modern functional imaging techniques (PET, CT and MRI) may help to assess rupture risk. Elective repair of AAA with open surgery or endovascular aortic repair (EVAR) should be considered to prevent AAA rupture, although the morbidity and mortality associated with both techniques remain non-negligible. An abdominal aortic aneurysm (AAA) is an enlargement of the abdominal aorta. As the AAA grows, the aortic wall becomes progressively thin, and the risk of rupture increases; AAA rupture causes severe intra-abdominal haemorrhage and has a very high mortality.

Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets. Aortic aneurysm and dissection, the major problem linked to Marfan syndrome (MFS), lacks effective pharmacological treatment. Here, the authors show that the NO pathway is overactivated in MFS and that inhibition of guanylate cyclase and cGMP-dependent protein kinase reverts MFS aortopathy in mice.

Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRNAs) are crucial regulators of cardiovascular pathology and represent intriguing targets to limit AAA expansion. Here we show, by using two established murine models of AAA disease along with human aortic tissue and plasma analysis, that miR-24 is a key regulator of vascular inflammation and AAA pathology. In vivo and in vitro studies reveal chitinase 3-like 1 (Chi3l1) to be a major target and effector under the control of miR-24, regulating cytokine synthesis in macrophages as well as their survival, promoting aortic smooth muscle cell migration and cytokine production, and stimulating adhesion molecule expression in vascular endothelial cells. We further show that modulation of miR-24 alters AAA progression in animal models, and that miR-24 and CHI3L1 represent novel plasma biomarkers of AAA disease progression in humans. Abdominal aortic aneurysm (AAA) is a potentially fatal and often asymptomatic disease whose causes remain unclear. Here the authors show that a microRNA, miR-24, and its target, the glycoprotein chitinase 3-like 1, represent key regulators of AAA development.

Imaging software have become critical tools in the diagnosis and the treatment of abdominal aortic aneurysms (AAA). The aim of this study was to develop a fully automated software system to enable a fast and robust detection of the vascular system and the AAA. The software was designed from a dataset of injected CT-scans images obtained from 40 patients with AAA. Pre-processing steps were performed to reduce the noise of the images using image filters. The border propagation based method was used to localize the aortic lumen. An online error detection was implemented to correct errors due to the propagation in anatomic structures with similar pixel value located close to the aorta. A morphological snake was used to segment 2D or 3D regions. The software allowed an automatic detection of the aortic lumen and the AAA characteristics including the presence of thrombus and calcifications. 2D and 3D reconstructions visualization were available to ease evaluation of both algorithm precision and AAA properties. By enabling a fast and automated detailed analysis of the anatomic characteristics of the AAA, this software could be useful in clinical practice and research and be applied in a large dataset of patients.