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Large Vessel Cell Heterogeneity and Plasticity: Focus in Aortic Aneurysms

Originally published, Thrombosis, and Vascular Biology. 2022;42:811–818


Smooth muscle cells and endothelial cells have a remarkable level of plasticity in vascular pathologies. In thoracic and abdominal aortic aneurysms, smooth muscle cells have been suggested to undergo phenotypic switching and to contribute to degradation of the aortic wall structure in response to, for example, inflammatory mediators, dysregulation of growth factor signaling or oxidative stress. Recently, endothelial-to-mesenchymal transition, and a clonal expansion of degradative smooth muscle cells and immune cells, as well as mesenchymal stem–like cells have been suggested to contribute to the progression of aortic aneurysms. What are the factors driving the aortic cell phenotype changes and how vascular flow, known to affect aortic wall structure and to be altered in aortic aneurysms, could affect aortic cell remodeling? In this review, we summarize the current literature on aortic cell heterogeneity and phenotypic switching in relation to changes in vascular flow and aortic wall structure in aortic aneurysms in clinical samples with special focus on smooth muscle and endothelial cells. The differences between thoracic and abdominal aortic aneurysms are discussed.


  • Review of aortic smooth muscle cell and endothelial cell heterogeneity and phenotypes, for example, degradative smooth muscle cells, mesenchymal stem like smooth muscle cells, and mesenchymal-like endothelial cells, found in aortic aneurysm patients by single-cell RNA sequencing with suggested association to aortic wall remodeling and a risk of dissection/rupture.

  • Overview on what is known about the relation of the aortic cell phenotypes, plasticity, genetics and hemodynamics in thoracic and abdominal aortic aneurysms in patients.

  • Perspective how single-cell RNA sequencing data should be used to understand disease pathogenesis of aortic aneurysms and develop precision medicine to patient subgroups.

  • Emphasis on a need for further experiments to demonstrate connection between smooth muscle cell and endothelial cell phenotype switching to the disease pathology in patient samples.

The prevalence of aortic aneurysms is between 1.3% and 9%, affecting predominantly males.1,2 Aortic aneurysms can occur either in thoracic or abdominal aorta. They often grow asymptomatically, making aneurysms difficult to detect. In thoracic aortic aneurysm (TAA), symptoms are secondary to aortic rupture or dissection, including sudden severe chest or back pain, hypotension, and possible hematemesis or hemoptysis, that is, vomiting or coughing of blood, respectively. In contrast to aortic rupture, aortic dissection involves disruption of the aortic medial layer, with intramural hemorrhage leading to propagation and tracking of blood within the media. In abdominal aortic aneurysm (AAA), growing of the aneurysm may cause abdominal pain or pulsative resistance near the midline. At present, no pharmacological therapy exists for TAA or AAA that would prevent aortic aneurysm growth or rupture/dissection, and the available therapies are limited to preventive medication, surgical and catheter-based interventions.1,2

Please see for all articles published in this series.

Thoracic and abdominal aorta have different developmental origins, flow patterns and structural differences of the aortic wall. As examples, thoracic aorta has a thicker medial layer, higher elastin and collagen amount but a thinner intimal layer compared to abdominal aorta. Altered wall shear stress (WSS), weakening of the aortic wall and medial degeneration, that is, loss and fragmentation of elastin fibers, increased expression of MMP (matrix metalloproteinases), and loss or hyperplasia of smooth muscle cells (SMCs) have been associated with both TAA and AAA.3–7 Atherosclerosis and chronic inflammation are associated with AAA. Instead, an increased accumulation of proteoglycans is characteristic of TAA.3

Recent single-cell RNA sequencing (scRNA-seq) data have shed light on the role and plasticity of aortic cells in aneurysms. SMCs have been suggested to undergo phenotypic switching due to, for example, oxidative stress, dysregulated growth factor signaling, Rho GTPase, inflammation, angiotensin II signaling, and epigenetic factors in aortic aneurysms,8–13 further contributing to degradation of the aortic wall structure. Involvement of endothelial cell (EC) dysfunction or endothelial-to-mesenchymal transition (EndMT) have also been suggested.14–17 Here, we summarize the current literature on aortic cell phenotypes and heterogeneity in relation to the changes in vascular flow and aortic wall structure in aortic aneurysms in clinical samples focusing on ECs and SMCs. Specific characteristics of TAA and AAA are discussed.

Cell Phenotypes and Plasticity

Most abundant cell types in the blood vessel wall, ECs and SMCs, show remarkable plasticity and heterogeneity. The highest proportion of these cells in healthy stabilized blood vessels represent quiescent phenotype, called phalanx EC or contractile SMC. This tissue and vessel type-specific nonproliferative cell stage is invaluable for normal vascular functions and is tightly regulated by WSS, growth factor stimuli, ECM (extracellular matrix) composition and other cell types.18,19 Contractile-to-synthetic phenotypic modulation of SMCs was earlier suggested to associate with both TAA and AAA.20,21 Recent scRNA-seq and lineage-tracing studies have revealed a broad range of additional phenotypes for SMCs and ECs in vasculature (reviewed in Yap et al,18 Ricard et al,19 Grootaert et al,22 Dejana et al23) and suggested phenotypic switching and clonal expansion of specific cell subtypes in aortic aneurysms.24,25

Smooth Muscle Cells

Earlier, injury, oxidative stress or inflammation were suggested to drive SMCs from contractile to proliferative/migratory, synthetic phenotype in aortic aneurysms,8,20,26,27 for example, due to defective elastin lamellae impairing attachment of SMCs or via increased production of MMPs. Based on current knowledge, presence of multiple SMC phenotypes in TAA is evident; however, how they associate with the disease progression in human, or whether alteration of all SMCs or a proportion of specific SMC subtype(s) occurs, is still largely unknown.

Besides contractile SMCs expressing ACTA2, ACTC1, and MYL9, Li et al24 identified 2 clusters of proliferating SMCs in patients with TAA that they suggested to play a role in adaptive response of the cells due to expansion of the aorta. These SMCs had increased expression of synthetic SMC markers (eg, MGP, TPM4, MYH10) and cyclin, but unlike traditional synthetic SMCs, the cells also expressed high levels of contractile SMC markers. More studies are needed to understand whether this SMC phenotype is associated with the change in the aortic diameter or medial degeneration in TAA.

Besides altered contractility properties, SMCs in aortic aneurysms are likely susceptive to apoptosis/senescence that can promote SMC loss and media thinning. In a study by Li et al,28 mTOR (mammalian target of rapamycin)-dependent proliferation of degradative SMCs, having proteolytic and phagocytic characteristics, was suggested to be a causal factor of TAA. In their study, a degradative SMC phenotype (Lamp2+ [lysosomal-associated membrane protein 2], Gal3+, Moma2+), distinguishable from macrophages, was demonstrated to be associated with SMC hyperplasia and progressive aortic degeneration in a mouse model with a conditional activation of mTORC1-signaling. LAMP2-positive SMCs were accordingly observed in TAA, and LAMP2 expression level correlated with a loss of elastin, medial thinning and number of medial cells.28 Clonal expansion of SMCs and phenotype switching from contractile to phagocytic was also detected in lineage-tracing studies by Clement et al11 in mice with angiotensin II–induced aortic dilatation, and a knock-out of autophagy-related factor Atg5 increased SMC apoptosis and drove more severe disease phenotype; thus, suggesting involvement of autophagy in the aortic degeneration. In the study of Li et al,24 trajectory analysis also suggested that SMCs could re-differentiate into inflammatory cells in TAA, although, a role of this cell phenotype in TAA pathogenesis remained unresolved.

Reprogramming of SMCs to mesenchymal stem cell (MSC)–like state has also been identified in scRNA-seq studies for TAA. This could act as a cellular dedifferentiation step for SMCs toward a more proliferative/migrative stage. In the study by Chen et al,29 loss of Tgf-β (transforming growth factor beta 1)-signaling output in SMCs resulted in transdifferentiation of subpopulation of MYH11-positive SMCs to MSC-like state (CD105+, CD73+, CD90+) and further to MSCs (aggrecan+, osteopontin+, adiponectin+, CD68+). Further bulk RNA sequencing on samples of dyslipidemic TAA patients showed reduced TGF-β signaling. Based on these data, a combination of reduced TGF-β signaling and hypercholesterolemia was suggested to induce development of TAA in patients with atherosclerosis.29 Dysregulation of TGF-β signaling was also detected in patients with Marfan syndrome (MFS).12 These SMCs expressed high levels of cyclin and a stem cell marker THY1, moderate levels of MYH11 and a fibroblast marker CYTL1. A MYH11-positive MSC-like cell cluster was also observed in TAA by Li et al.24 In TAA, the presence of this cell phenotype could lead to less stabilized aortic wall structure, and potentially influence the disease progression. However, further studies are needed to demonstrate the association of MSC-like cells or MSCs with, for example, media degeneration in the patient samples.

So far, limited scRNA-seq data exists from human AAA and the studies have not been focusing on defining SMC phenotypes but immune cells.10 Earlier, Zhao et al30 detected four SMC phenotypes in mice having elastase-induced infrarenal AAA. Three of these subpopulations were shown to decrease in time; however, a clonal expansion of a small subpopulation of SMCs was detected at the later stage of infrarenal AAA development. These modulated SMCs had decreased expression of contractile markers and increased expression of proinflammatory genes.30 Further studies are needed in AAA patient samples to understand whether clonal expansion of SMCs play a role in the disease progression.

Endothelial Cells

Most of the scRNA-seq studies on patient TAA show 2 to 3 distinct EC clusters.12,24 These clusters likely form, at least partly, due to different location of the ECs in the aortic wall, that is, intima versus adventitia, thus, predisposing them to distinct levels WSS or other mechanical/microenvironmental factors.31 Also, EndMT or endothelial dysfunction, have been reported in TAA/AAA.14,30 In EndMT, ECs acquire characteristics of mesenchymal cells, including their contractile function, increased expression of, for example, collagen and SMC markers TAGLN and ACTA2, accompanied with increased migratory properties, loosening of EC-EC junctions, and consequent increase in permeability and leukocyte infiltration across the endothelium. TGF-β signaling is the major driver promoting EndMT, together with, for example, disturbed blood flow, deregulation of NOTCH signaling, oxidative stress, and certain inflammatory cytokines. Part of these factors are also connected to endothelial dysfunction, characterized as a proinflammatory condition having upregulated expression of adhesion molecules and proinflammatory cytokines (presented as an inflammatory EC phenotype in the Graphical Abstract), increased permeability, and decreased responsiveness for vasodilation.14,16,17,23,30 See Table for more details about the SMC and EC phenotypes detected in TAA/AAA.

Table. Examples of Cell Phenotypes Identified in Patients With TAA and AAA

nSex (M/F)Age, yTAA/AAATAV/BAV/NA (n)Dyslipidemia (n)PhenotypeMarkerMethodReferences
11/025TAANANAModSMC, SMC and EC clusters, total 8 cell typesMultiple TGF-β signaling factorsscRNA-seqPedroza et al25
84/467.6±7.6TAA5/2/1NA5 SMC or SMC-like, 2 EC, 2 MSC/pericyte, 2 fibroblast, multiple immune-modulatory cell clusters, total 40 cell typesMultiple cell markersscRNA-seqLi et al24
31/233.7±9.3TAANANA6 SMC-like, 3 EC, 3 fibroblast, 2 MSC/pericyte, multiple immune cell clusters, total 18 clustersMultiple cell markersscRNA-seqDawson et al12
66/058.7±8.2TAANA5/6MYH11+ mesenchymal cell-like and MSC-like medial cellsaggrecan, OPN, ADIPOQ, CD68, CD105, CD73, CD90IHCChen et al29
1212/060.1±9.6TAA5/7/08/12Degradative SMCLAMP2IHCLi et al28
2424/068.0±6.1AAANA14/24Proliferative SMCiNOS, LOX, FBN1cell cultureFarrell et al13
2920/967.5±14.4TAANA7/29ACTA2+ SMCACTA2IHC, RT-qPCRTang et al7
2613/1363.1±11.8TAANA14/26Synthetic SMCOPN, MMP-9RT-qPCRBranchetti et al8
107/348.2±6.7TAA10/0/04/10Synthetic SMCOPNIHC, cell cultureWang et al27
2217/569.8±1.9AAANANAMMP-2+ and MMP-9+ SMCMMP-2, MMP-9RT-qPCR, Zymography, Western BlotAirhart et al6

AAA indicates abdominal aortic aneurysm; ACTA2, actin, aortic smooth muscle; ADIPOQ, adiponectin; BAV, bicuspid aortic valve; EC, endothelial cell; F, female; FBN1, fibrillin-1; IHC, immunohistochemistry; iNOS, nitric oxide synthase, inducible; LAMP2, lysosome-associated membrane glycoprotein 2; LOX, lysyl oxidase; M, male; MMP, matrix metalloproteinases; ModSMC, modulated SMCs; MSC, mesenchymal stem cell; MYH11, myosin-11; NA, not applicable; OPN or SPP1, osteopontin; RT-qPCR, quantitative reverse transcription polymerase chain reaction; scRNA-seq, single-cell RNA sequencing; SMC, smooth muscle cells; TAA, thoracic aortic aneurysm; TAV, Tricuspid aortic valve; and TGF-β, transforming growth factor-β.

Immune Cells

Recruitment of immune cells to aortic aneurysms has been associated with increased production of MMPs, thus being able to remodel the aortic wall. Recent scRNA-seq study by Davis et al10 on AAA patient demonstrated a subgroup of monocytes/macrophages with increased expression of an epigenetic enzyme JMJD3 (jumonji domain-containing protein-3) that drives activation of NF-κB (nuclear factor κB) signaling and upregulation of inflammatory mediators. In addition to macrophages, clonal expansion of infiltrated T cells was suggested in the pathological areas of aortic wall in AAA.32,33 Participation of immune cells has been studied also in TAA. Li et al24 identified a higher proportion of T-lymphocytes in TAA than control aorta. Interestingly, a smaller proportion of cells in proliferative phase was detected in TAA than controls, which, on the contrary to AAA, suggests infiltration of T cells to the diseased aorta instead of their proliferation in situ.24

Genetics and Cell Plasticity

Certain genetic factors and syndromes are associated risk factors in both TAA and AAA (for a comprehensive review, see, eg, Pinard et al34 and Huang et al35). Although the majority of TAAs are sporadic, 20% of them are caused by inherited mutation in a single risk gene, related to TGF-β signaling, SMC cytoskeletal/contraction proteins, ECM/connective tissue, or development either as part of a syndrome (MFS; Loyes-Dietz syndrome; or vascular-type Ehlers-Danlos syndrome) or as an isolated disease. Even a broader range of somatic mutations have been detected in a sporadic TAA; although, a list of risk genes and affected signaling pathways is partly overlapping with the syndromic and nonsyndromic familial TAAs.36,37

In AAA, genetic studies have identified 87 genes or loci with polymorphisms on AAA patients but only 10 of them with strong or moderate evidence for association with the disease. These are related to cholesterol metabolism, atherosclerosis, inflammation, and hypertension.38 Overall, although genetics behind AAA have been intensively studied and AAA cases shown to accumulate in certain families, multifactorial nature of AAA makes it less predictable than TAA. Genetic variation in the risk genes or loci, in combination with environmental/lifestyle factors, has been concluded to have joint effect on disease onset and development.34

In mice, point mutations or knock-out of genes, for example, Fbn1 and Tgfbr2, have been used to induce aortic dilatation and have demonstrated the SMC plasticity and heterogeneity in murine aneurysms and lately, endothelium dysfunction25,29,39,40 (for a comprehensive review, see, eg, Lu et al41, and Patelis et al42). As examples, modulated SMCs, detected in larger proportion in Fbn1 knock-out than control mice, showed intermediate expression of contractile SMC markers, together with high expression of fibronectin 1, Mgp, Nupr1, and elastin, indicating that these cells were undergoing phenotype switching from contractile SMCs towards fibroblasts. In patients, however, most of the gene expression analyses have been done without knowing the patients’ genetic background. Thus, a limited knowledge exists on how a specific genetic mutation affects aortic cell plasticity in humans. In the study of Pedroza et al.25 modulated SMCs with increased expression of markers of TGF-β-signaling (CTGF, SERPINE1, TGFB1), were detected in a patient with MFS (n=1) carrying mutation in FBN1. Pedroza et al.25 also compared patient data to the scRNA-seq data from a murine aneurysm model, and showed that contrary to observations in mice, for example, ACE was not expressed in modulated SMCs in a MFS patient.25 Thus, the data highlighted the importance of studying disease mechanisms in patient samples to identify therapeutic targets. Besides SMCs, endothelial etiology was demonstrated in TAA patients with a bicuspid aortic valve, that is, an abnormal aortic valve anatomy induced by mutation in ROBO4, and EndMT was suggested as the driver of pathological changes.14 Further studies are required to understand the association of cell plasticity/heterogeneity with genetics in aortic aneurysms in patients.

Epigenetics and Cell Plasticity

Cell phenotypes in aortic aneurysms can also be affected by epigenetic modifications, that is, DNA methylation, histone modifications, and noncoding RNA (for detailed review, see Mangum et al43 and Boileau et al44). Although, modulation of immune cell, SMC and EC gene expression and cellular function, promoted by epigenetic regulators and with potential consequences on TAA/AAA progression, have been extensively studied in cells and murine aneurysm models, limited knowledge exists from patients. Increased expression of histone deacetylases was detected in SMCs and T cells in AAA patients, and their inhibition in SMCs in vitro and in hypercholesterolemic mice abrogated angiotensin II–induced inflammatory SMC phenotype and expression of inflammatory markers, MMPs and AAA expansion.45 Reduced expression of a long noncoding RNA ANRIL was also found in AAA, with effects on SMC dedifferentiation or apoptosis.46 In TAA, alteration in histone modifications was also shown to lead to dysregulation of SMAD2 and overexpression of certain serine proteases that could affect aortic wall degeneration.47–49

What About Hemodynamics?

Besides genetics, WSS can influence heterogeneity and plasticity of the cells in the vessel wall. Laminar flow is a key for maintaining normal vascular function and quiescent phenotypes, that is, phalanx EC and contractile SMCs in aorta. In various in vitro models, flow-induced shear stress has been shown to affect signaling of ECs and SMCs, either directly or via cellular crosstalk, and to induce SMC phenotype modulation, altered gene expression or re-organization of the cellular cytoskeleton.50–53 Laminar flow-induced EC polarization and alignment to the direction of flow is evident, and recently Kant et al.53 demonstrated involvement of PGC1α-TERT-HMOX1 pathway in this response. Also, for example, PGI2 and other factors secreted by ECs under laminar flow can control phenotypic modulation of SMCs towards contractile stage.52

Decreased WSS or oscillatory flow have been associated with many pathologies and also, modulation of EC and SMC phenotypes. For example, in a partial carotid ligation model, disturbed blood flow induced EC phenotype switch from antiatherogenic to inflammatory, immune cell-like and mesenchymal-like ECs.54 Also, in a similar study, a SMC cluster with upregulated expression of genes related to SMC migration, osteoblast differentiation, and profibrosis was found that could contribute to arterial stiffening. Additional EC clusters, expressing genes related to EndMT, integrin activation, and TGF-β production were shown to locate in areas with disturbed flow together with activated macrophages and infiltrated T cells.55

In terms of aneurysms, only limited data exist on the potential role of WSS in inducing cell phenotype switching or heterogeneity. In patients with intracranial aneurysm, expression of contractile SMC proteins was decreased in regions with low WSS, whereas SDF-1α/CXCR4 signaling, MMP-2, and TNF-α were upregulated.56 In TAA, we and others have suggested altered WSS to induce structural and cellular changes in the aortic wall,57–61 for example, reduced amounts of elastin and SMCs,62 thinner elastic fibers,63 that is, features that have been associated with stiffer, more fragile aortic tissue. However, how WSS affects, for example, presence of synthetic or degradative SMC phenotypes in TAA is still unknown. In-line with studies in mouse models,54,55 altered WSS has shown to increase endothelium permeability, expression of inflammatory adhesion molecules, EndMT-related markers and intimal thickening also in patients with TAA.14,64,65 Interestingly, previous studies have shown that TAA patients with bicuspid aortic valve have altered hemodynamics (eg, higher WSS)66 and increased rate of SMC apoptosis in comparison to patients with TAA and normal tricuspid aortic valve anatomy.67 This implies that altered flow patterns could affect SMCs in TAA, and unlike currently, bicuspid aortic valve and tricuspid aortic valve should be analyzed as separate patient subgroups in scRNA-seq studies to pinpoint their specific disease mechanisms.

Similar to TAA, altered hemodynamics has been associated with aneurysm growth, aortic wall structural changes and rupture in AAA.68–70 The association between cells, biomechanical changes and WSS is so far largely unknown. Interestingly, Piezo1, a mechanosensory ion channel, known to be activated by shear stress, was recently suggested to regulate AAA development in mice and to be expressed in SMCs in both mouse and human AAA.71 Further scRNA-seq experiments will likely bring more insight on regulation of cell plasticity and heterogeneity by WSS in aortic aneurysms.

Management and Future Prospects

The current standard of evaluating the risk for aortic rupture is based on the diameter of aorta and the change of the diameter. The growth rate of aortic aneurysm, however, continues to be difficult to predict, and patients are followed with ultrasound (AAA) or computed tomography and magnetic resonance imaging (TAA) annually or after 2 to 3 years, depending on the clinical risk evaluation of an individual patient.72,73 If intervention is required, TAA is operated with open surgery, whereas AAA is either treated with endovascular aneurysm repair or combination of endovascular aneurysm repair with open surgery.72,73 Although immediate surgery improves the prognosis of patients with aortic dissection/rupture, operative mortality remains at about 25%.74

The main aim of the current medical therapy for aortic aneurysms is to reduce shear stress on a diseased segment of the aorta by reducing blood pressure and cardiac contractility. Based primarily on studies performed on patients with MFS, beta blockers, ACE (angiotensin-converting enzyme) inhibitors, or angiotensin receptor blockers are recommended for controlling blood pressure on patients with asymptomatic TAA under conservative management. However, there is currently no evidence for the efficacy of these treatments in TAA of any other etiologies than MFS.73,75 Based on the new findings on mTOR-dependent proliferation of degradative SMCs in aortic aneurysms and effective prevention of murine aneurysm formation by mTOR-targeting rapamycin, this pathway could be a potential target for medical therapy of TAA.28 In addition, gene-set enrichment analysis and genome-wide association to TAA-related SNPs (single nucleotide polymorphism) have demonstrated transcription factor ERG as a novel target with a protective role against TAA.24

In terms of AAA, having etiology more prominently affected by atherosclerosis, current treatment is primarily targeted against the common cardiovascular risk factors. Besides treating blood pressure with ACE inhibitors or angiotensin receptor blockers, several clinical studies suggest that statins inhibit the expansion of AAA and prevent its rupture.73,76 Based on mouse studies, targeting of JMJD3 pathway that regulates inflammation in AAA, or Piezo1 antagonists in combination with surgical interventions could be potential new therapies to reduce or stabilize the aneurysm growth.10,71

Improved imaging modalities have enabled more detailed knowledge about the role of WSS in aneurysm pathobiology and growth. Our recent work demonstrated association of decreased WSS with significant growth of TAA and suggested 4-dimensional flow magnetic resonance imaging as useful in assessing risk for AA diameter growth.77 We and others62–64 have also studied how WSS induces changes in the biomechanical properties and cellular heterogeneity of the aorta in patients with TAA and shown high region-specificity. It remains to be seen whether WSS is also able to contribute to reprogramming of SMCs, immune cells, and ECs in aortic aneurysms, how these relate to aortic expansion, and how different genetic factors affect growth rate of the aneurysms in human. Although heterogeneity and focality of histopathologic changes in aortic aneurysms are evident, most of the studies from clinical samples are performed on 1-2 small regions of the aorta with unknown histopathology. This region-specific variability and a lack of proteomics data can lead to biased interpretation of disease-specific signaling pathways. In addition, samples from patients with different genetic background, valve anatomy, ethnicity, medication, and sex are often combined in the same scRNA-seq analysis, with an effect on data interpretation. Artifacts caused by sample handling could also affect the data, for example, a stressed SMC cluster expressing many of the early stress response genes (FOS, ATF3, JUN, HSP8) has been detected in several scRNA-seq studies12,24 and instead of being a real separate cluster, could be caused by enzymatic processing of the tissue.78 So far only a few studies have shown how scRNA-seq findings or cell clusters associate with medial degeneration or the aortic diameter in the studied region. In understanding the role of cell populations and their function in TAA/AAA pathobiology, spatial relation of the cell populations in context of aortic histopathology, expansion and WSS is required.

To conclude, due to risk of serious complication, development of medical treatment, accurate diagnosis at early stage and optimal timing of surgical intervention are essential to prevent adverse events and to reduce mortality in patients with aortic aneurysm. Currently, the therapies of aortic aneurysms are limited to preventive medication in addition to surgical and catheter-based interventions. Together with increasing knowledge of relation of genetics, disease mechanisms, histopathologic processes of the aortic wall and region-specific flow conditions inside the aneurysm, more personalized and tailored therapies can be developed against the progression of aneurysm growth and rupture. Future studies should focus more on patient subgroups enabling the development of targeted therapies.

Article Information


Schematic illustrations were created with under an academic postdoc license.

Nonstandard Abbreviations and Acronyms


abdominal aortic aneurysm


angiotensin-converting enzyme


endothelial cell


extracellular matrix


endothelial-to-mesenchymal transition


Marfan syndrome


matrix metalloproteinase


mesenchymal stem cell


single-cell RNA sequencing


smooth muscle cell


thoracic aortic aneurysm


wall shear stress

Disclosures None.


For Sources of Funding and Disclosures, see page 816.

Correspondence to: Johanna Laakkonen, PhD, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, FI-70210 Kuopio, Finland. Email


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