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Pathophysiology of Thoracic Aortic Aneurysm

TL;DR — TAA is a disease of the aortic media, not the intima. The canonical lesion — historically "cystic medial necrosis," now formally renamed by consensus to mucoid extracellular matrix accumulation (MEMA) + elastic fibre fragmentation/loss + smooth muscle cell nuclei loss (Halushka 2016, PMID 27031798) — reflects failure of the elastin-contractile unit, the mechanical continuum linking elastic lamellae → fibrillin-1 microfibrils → integrin focal adhesions → SMC actomyosin (Karimi 2015, PMID 26724508). Nearly every gene causing heritable TAA encodes a component of that continuum or of the TGF-β pathway that regulates it. The field's central unresolved problem is the TGF-β paradox: loss-of-function mutations in FBN1, TGFBR1/2, and SMAD3 should reduce TGF-β signalling, yet aneurysmal tissue and mouse aortas show increased signalling (Neptune 2003, PMID 12598898; Habashi 2006, PMID 16601194) — while SMC-specific deletion of the TGF-β receptor worsens aortopathy (Li 2014, PMID 24401272; Wei 2017, PMID 28119285), implying much of the excess signalling is compensatory rather than causal. Unlike AAA, TAA is predominantly non-atherosclerotic and only modestly inflammatory, though T-cell and macrophage infiltrates are demonstrable and correlate inversely with age at repair (He 2008, PMID 18954631). Segment specificity tracks the embryologic mosaic of the ascending aorta — cardiac neural crest inner media, second heart field outer media (Sawada 2017, PMID 28663257) — and disease in humans and in angiotensin II mice is concentrated in the SHF-derived outer layers (Sawada 2022, PMID 35143327).

1. The medial lesion: what "cystic medial necrosis" actually is

The 2016 SCVP/AECVP consensus abolished the terms cystic medial necrosis and medionecrosis — there is neither a true cyst nor necrosis — and replaced them with a graded, descriptive vocabulary (Halushka 2016, PMID 27031798). Inflammatory aortic disease (aortitis, periaortitis, inflammatory atherosclerotic aneurysm) is handled by a separate consensus document and is a distinct differential, not part of the degenerative TAA lesion (Stone 2015, PMID 26051917).

Consensus term Substrate Retired synonyms
Mucoid extracellular matrix accumulation (MEMA) Pooled glycosaminoglycans/proteoglycans displacing lamellae "cystic medial necrosis", "cystic medial degeneration", mucoid degeneration
Elastic fibre fragmentation and/or loss Broken, thinned, splayed elastic lamellae elastic fibre degeneration, elastolysis
Smooth muscle cell nuclei loss Focal/banded/laminar dropout of medial SMCs "medionecrosis", SMC necrosis
Laminar medial collapse Approximation of adjacent lamellae after elastin loss —
Overall medial degeneration (graded) Composite severity score "medial degeneration grade I–III" (legacy schemes)

Blinded application of this scheme to 148 surgically resected ascending specimens showed that histopathologic pattern partially discriminates aetiology: unsupervised clustering separated bicuspid-aortic-valve and non-syndromic cases from Marfan and Loeys–Dietz cases, with Marfan showing significantly more overall medial degeneration and more MEMA than other groups (Waters 2017, PMID 28646716). Critically, SMC nuclei loss was a feature of ageing, not of Marfan or Loeys–Dietz — a warning against reading SMC dropout as a syndromic signature (PMID 28646716).

Of the four canonical features, GAG/proteoglycan pooling appears comparatively specific to thoracic aneurysm/dissection rather than being a generic degenerative change (Humphrey 2012, PMID 23018968). Its mechanical consequences are treated in hemodynamics and biomechanics.

2. Extracellular matrix homeostasis and the elastin-contractile unit

The medial lamellar unit is an alternating stack of elastic lamellae and SMCs. The elastin-contractile unit is the functional through-line across that stack (Karimi 2015, PMID 26724508):

  1. elastin fibres ensheathed by fibrillin-1 microfibrils;
  2. microfibrils engaging integrin receptors at SMC focal adhesions;
  3. focal adhesions coupled on the cytoplasmic face to SMC contractile filaments.

The genetic argument for this being the disease unit is that the genes causing heritable TAA map onto its parts (PMID 26724508; reviewed Rodrigues Bento 2022, PMID 36044906):

Compartment Genes Encoded role
Elastic fibre / microfibril FBN1, ELN, MFAP5, FBLN4 (EFEMP2) Microfibril scaffold, tropoelastin deposition, cross-linking support
Force transmission FLNA Filamin A links integrin receptors to contractile filaments
Contractile apparatus ACTA2, MYH11 SMC α-actin, SM myosin heavy chain
Contraction regulation MYLK, PRKG1 Myosin light chain kinase; cGMP-dependent protein kinase
TGF-β pathway TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3 Receptor/effector cascade (Loeys–Dietz spectrum)

Fibrillin-1 is not merely structural scaffolding. Gene-targeting in mice showed that fibrillin-1 microfibrils are "predominantly engaged in tissue homeostasis rather than elastic matrix assembly," implying aortic dilatation follows failure of the microfibrillar array to sustain physiologic haemodynamic stress, with disruption of the medial elastic network as a secondary event (Pereira 1997, PMID 9326947). Allelic series in mice further establish a threshold effect: phenotypic severity scales with the level and integrity of microfibrils rather than with the presence of a mutant protein per se (Pereira 1999, PMID 10097121; Ramirez 1999, PMID 10442675), and haploinsufficiency for wild-type fibrillin-1 — not dominant-negative action of mutant protein — is the primary determinant of failed microfibrillar assembly, since a wild-type FBN1 transgene rescues the aortic phenotype of Fbn1^C1039G/+ mice (Judge 2004, PMID 15254584).

Fibrillin-1 also anchors an outside-in mechanosensing interface. Fibronectin is elevated in the tunica media of human Marfan and non-syndromic thoracic aneurysms and in Fbn1^mgR/mgR mouse aortas; replacing the integrin α5 cytoplasmic tail with that of integrin α2 (α5/2 chimera) markedly prolonged survival of mgR mice and preserved elastic fibre integrity, SMC density and contractile gene expression, with NF-κB activation as the downstream node (Chen 2023, PMID 36994727).

3. Proteolysis: MMP/TIMP balance

Matrix turnover in TAA is dysregulated in both directions — not simply "more proteolysis."

Study Tissue Key quantitative findings
Lesauskaite 2001 (PMID 11567232) Human ascending aorta: aneurysm, dissection, post-valvular dilatation vs CABG controls Medial SMCs showed stronger immunoreactivity for MMP-1, MMP-2, MMP-9 and TIMP-1, TIMP-2 than controls; increased osteopontin and synthetic-phenotype ultrastructure; SMC density not significantly reduced overall; no apoptosis detected by ISEL/DNA laddering
Ikonomidis 2006 (PMID 16820601) Marfan (n=9) vs non-Marfan (n=18) ascending aneurysm vs non-aneurysmal controls (n=18) Marfan: MMP-2 decreased to 76±7% of control; MMP-12 161±27%; MT1-MMP 248±64%; TIMP-3 74±23%; TIMP-2 128±31% vs non-Marfan 73±19%; TGFBR2 193±32%
Huusko 2012 (PMID 22571802) Plasma + aortic tissue, ascending and abdominal aneurysm Plasma osteopontin, MMP-2, MMP-9 elevated vs controls in both territories; aortic mRNA for the same three increased in ascending aneurysm
Guzzardi 2015 (PMID 26293758) Paired within-patient BAV ascending samples, high- vs normal-WSS regions High-WSS regions: ↑TGF-β1 (p=0.04), ↑MMP-1 (p=0.03), ↑MMP-2 (p=0.06), ↑MMP-3 (p=0.02), ↑TIMP-1 (p=0.04)

Two points follow. First, the MMP/TIMP portfolio is aetiology-specific: the Marfan profile (low MMP-2, high MT1-MMP and MMP-12, low TIMP-3) differs from the non-syndromic profile in the same study, in which most MMPs were reduced relative to non-aneurysmal control aorta (PMID 16820601). Second, proteolytic dysregulation is regionally patterned within a single aorta and co-localises with mechanical load (PMID 26293758) — see hemodynamics and biomechanics.

Cross-linking is the mirror image of proteolysis. Genetic ablation of lysyl oxidase produces perinatally lethal aortic aneurysms with fragmented elastic fibres and discontinuous SMC layers (Mäki 2002, PMID 12417550), and pharmacologic LOX inhibition is the basis of the BAPN lathyrism models described in animal models. Ciprofloxacin, which suppresses lysyl oxidase expression, accelerated aortic enlargement and raised dissection (25%→47%, p=0.03) and rupture (5%→25%, p=0.005) rates in Marfan mice (LeMaire 2020, PMID 34586071) — a rare instance where a mouse mechanism maps directly onto a clinical drug caution (see medical therapy).

4. Smooth muscle cell phenotype and loss

Medial SMCs in TAA undergo phenotypic modulation away from a contractile state. Human ascending aneurysm, dissection and post-stenotic dilatation tissue shows synthetic-phenotype ultrastructure and increased osteopontin in the media (PMID 11567232). Single-cell transcriptomics gives the modern, quantitative version: in Fbn1^C1041G/+ mice a discrete modSMC cluster appears in adult aortic root/ascending aneurysm tissue and is absent from wild-type aorta, from young mutant aortas (despite small aneurysms already being present), and from non-dilated descending thoracic aorta of the same animals; 481 genes are differentially expressed between modSMC and SMC, dominated by ECM modulation, collagen synthesis, adhesion and proliferation, with Serpine1 (PAI-1) and Klf4 forming a Marfan-specific signature distinct from the atherosclerotic (ApoE^−/−) modulation programme. The same modulated state was recovered from human Marfan aortic root surgical specimens, and TGF-β–responsive gene enrichment tracked the modulation (Pedroza 2020, PMID 32698686).

Importantly the dominant modulating cell type is disease-specific. In a Tgfbr1 Loeys–Dietz mouse model and in human LDS surgical specimens, no distinct modSMC cluster emerged; instead adventitial fibroblasts converted to a pro-inflammatory, chemokine-secreting state (Ccl2 and related), accompanied by a ~6-fold increase in aortic wall macrophage content (Dalal 2025, PMID 40109260). Marfan and Loeys–Dietz aortopathy therefore converge morphologically but diverge cellularly.

SMC dropout itself proceeds through several regulated death programmes — apoptosis, necroptosis, pyroptosis and ferroptosis are all implicated in aneurysm and dissection, and each is a candidate pharmacologic target (Chakraborty 2021, PMID 34597613). Note the tension with older histology: SMC nuclei loss is age-associated rather than syndrome-associated (PMID 28646716), and at least one careful ultrastructural study found no detectable apoptosis in human thoracic aneurysm media (PMID 11567232).

Loss of contractile function has a direct mechanical reading. Mutations in ACTA2 account for ~14% of inherited ascending TAAD, and affected aortas show medial degeneration, focal medial SMC hyperplasia and disarray, and stenotic vasa vasorum from medial SMC proliferation (Guo 2007, PMID 17994018). The unifying interpretation — that these genes converge on dysfunctional mechanosensing and mechanoregulation of the ECM rather than on a single biochemical pathway — is developed in Humphrey 2014 (PMID 24786066) and Humphrey 2015 (PMID 25858068).

5. The TGF-β story and its paradox

5.1 How the model was built

Year Observation Citation
1997 Targeted Fbn1 disruption: microfibrils serve tissue homeostasis more than elastogenesis PMID 9326947
1999 Fbn1^mgR/mgR underexpression → dissecting aneurysm with medial calcification, inflammatory-fibroproliferative response, inflammation-mediated elastolysis PMID 10097121
2003 Fibrillin-1–deficient mice show marked dysregulation of TGF-β activation and signalling; perinatal TGF-β antagonism rescues alveolar septation → matrix sequestration of cytokines regulates their activation PMID 12598898
2004 Haploinsufficiency, not dominant-negative mutant protein, drives failed microfibrillar assembly; WT transgene rescues aorta PMID 15254584
2006 Aneurysm in Fbn1^C1039G/+ associated with increased TGF-β signalling and prevented by TGF-β–neutralising antibody or by losartan (AT1 blockade) PMID 16601194
2006 TGFBR1/TGFBR2 heterozygous mutations cause Loeys–Dietz syndrome — aggressive aneurysm, mean age at death 26.0 years PMID 16928994

The 2003 → 2006 sequence is the origin of the modern pharmacology of aortopathy: if fibrillin-1 normally sequesters latent TGF-β, then fibrillin-1 deficiency liberates it, and blocking it should work. Losartan cured the mouse.

5.2 Why it is a paradox

The Loeys–Dietz genetics broke the simple model on arrival: mutations that impair TGF-β receptor function produce aortas with increased TGF-β signalling markers (PMID 16928994). Subsequent loss-of-function experiments made the contradiction sharper:

  • SMC-specific Tgfbr2 deletion in postweanling mice caused the thoracic aorta to rapidly thicken, dilate and dissect. Canonical Smad signalling fell as predicted, but MAPK signalling rose; disease arose from a perturbed contractile apparatus in medial cells plus growth-factor production by adventitial cells, i.e. maladaptive medial–adventitial paracrine crosstalk. Rapamycin restored a quiescent SMC phenotype and prevented dissection. The same deletion accelerated aneurysm growth on a Marfan background (Li 2014, PMID 24401272).
  • In young Fbn1^C1041G/+ mice, TGF-β signalling in aortic SMCs was not detectably altered, yet aortopathy developed; superimposed SMC-specific Tbrii deletion exacerbated both dilatation and medial disruption (Wei 2017, PMID 28119285).
  • Systemic TGF-β neutralisation and SMC-specific TGF-β signalling loss have opposite territorial effects: systemic blockade significantly increased angiotensin II–induced abdominal aneurysm prevalence, with non-significant trends toward greater severity, adventitial thickening and macrophage accumulation, while SMC-intrinsic loss significantly accelerated thoracic pathology (intramural haematoma, medial thinning, adventitial thickening). TGF-β protects both territories, by SMC-extrinsic mechanisms abdominally and SMC-intrinsic mechanisms thoracically (Angelov 2017, PMID 28729364).

5.3 Current readings of the paradox

Three non-exclusive interpretations are in play:

  1. Timing/compensation. Excess TGF-β signalling is a late, largely compensatory response to a wall already failing mechanically, not the initiating lesion — consistent with normal SMC TGF-β signalling in young Marfan mice (PMID 28119285) and with basal TGF-β being required for postnatal aortic homeostasis (PMID 24401272).
  2. Compartment and cell-type specificity. "TGF-β signalling" measured on a whole-aorta lysate conflates SMC, adventitial fibroblast and macrophage responses that move in different directions (PMID 28729364; PMID 40109260).
  3. Downstream non-canonical branches. Loss of Smad signalling with gain of MAPK signalling (PMID 24401272) means receptor-level loss-of-function and pathway-level gain-of-function are not contradictory at all.

A mechanistically adjacent proposal is that increased TGF-β drives the glycosaminoglycan pooling that is the most TAAD-specific histologic feature, and that GAG pools then act mechanically — reducing tensile strength, concentrating stress and raising intralamellar swelling pressure — to nucleate delamination (Humphrey 2012, PMID 23018968). This reframes the "paradoxical" fibrotic cytokine in a degenerative disease as a mechanical rather than purely biochemical actor.

The clinical epilogue — that losartan did not reproduce its mouse effect in humans (Lacro 2014, PMID 25405392; meta-analysis Kang 2019, PMID 31003918) — is covered in medical therapy and the model-side interpretation in animal models. The most recent synthesis frames the open task as sorting the hundreds of differentially expressed genes in the Marfan aorta into protective compensations, pathologic consequences, and neutral changes, so that therapy promotes the first and blocks the second (Humphrey 2026, PMID 42140666).

6. Inflammation: TAA is not AAA

The two aneurysm territories are frequently discussed as one disease and are not.

Axis Ascending TAA AAA
Dominant histology Non-inflammatory medial degeneration: MEMA, elastic fibre fragmentation, SMC nuclei loss (PMID 27031798) Transmural inflammation, adventitial thickening, intraluminal thrombus, atherosclerosis
Atherosclerosis Not the primary substrate; inflammatory/atherosclerotic aneurysm is classified separately (PMID 26051917) Central; the classic model in mice is AngII in ApoE^−/− hyperlipidaemic animals (PMID 26064906)
Genetic contribution High; monogenic in a substantial minority (PMID 36044906) — see genetics of TAA Lower penetrance, polygenic/environmental (smoking)
TGF-β blockade effect in mice SMC-intrinsic loss worsens thoracic disease Systemic blockade worsens abdominal disease via SMC-extrinsic route (PMID 28729364)
Standard mouse induction Genetic (Fbn1, Tgfbr, Acta2, Myh11), BAPN ± AngII Elastase perfusion; AngII in ApoE^−/− (PMID 26064906)

"Non-inflammatory" is a relative statement, not an absolute one. Immunohistochemistry of full aortic segments from Marfan (n=5), familial TAA (n=6) and sporadic TAA (n=9) versus control aortas (n=5) showed increased T lymphocytes and macrophages in both media and adventitia across all three aneurysm groups; the density of medial T cells and macrophages correlated inversely with patient age at prophylactic repair, i.e. the earliest-presenting, most aggressive aortas were the most inflamed. T-cell receptor β-chain variable region profiling suggested a similar clonal T-cell population across syndromic, familial and sporadic disease, raising a superantigen-driven hypothesis (He 2008, PMID 18954631). In Loeys–Dietz mice and human LDS tissue, macrophage content rose ~6-fold and adventitial fibroblasts adopted an explicitly pro-inflammatory chemokine programme (PMID 40109260). Inflammation is also a candidate mechanism by which homeostatic negative feedback in the arterial wall is overridden and replaced by positive feedback loops that drive maladaptive remodelling (Humphrey 2021, PMID 34255994).

7. Embryology and regional heterogeneity

TAA is strikingly segment-specific: aortopathy clusters at the root and ascending aorta and stops, roughly, at the ligamentum. The ascending aortic media is an embryologic mosaic, and this is the leading structural explanation.

  • Lineage tracing with Wnt1-Cre (cardiac neural crest, CNC) and Mef2c-Cre (second heart field, SHF) in mice showed both lineages populate the ascending media. CNC-derived cells occupy the inner medial aspect of the anterior ascending aorta and are transmural posteriorly; SHF-derived cells form a sleeve of outer medial cells throughout the anterior and posterior ascending aorta. CNC labelling extended from proximal ascending to just distal to the subclavian; SHF labelling extended from the aortic root throughout the ascending aorta. The distribution was independent of sex and ageing (Sawada 2017, PMID 28663257).
  • That anatomy predicts the pathology. In human ascending aneurysm tissue, degeneration was predominant in the outer medial layers and adventitia, a gradient mimicked in angiotensin II–infused mice and coincident with SHF-derived cell distribution. SHF-specific Lrp1 deletion augmented AngII-induced ascending aneurysm and rupture; SHF-specific Tgfbr2 deletion was embryonically lethal at E12.5 with a dilated outflow tract and retroperitoneal haemorrhage. PAI-1 was the most increased protein in SHF-derived SMCs and fibroblasts and showed a transmural gradient in both mouse and human aneurysmal aorta mirroring the pathology gradient (Sawada 2022, PMID 35143327).

The lineage story is, however, being complicated rather than confirmed by single-cell data. Comparing Nkx2-5-lineage (cardiac) and Wnt1-lineage (neural crest) SMCs in adult mice, both contributed to one major common cluster plus a minor lineage-specific cluster each; the neural-crest subset cluster was restricted to the arch (not the root) and showed greater expression of a subgroup of TGF-β–dependent genes — but conditional TGF-β receptor deletion produced similar transcriptional changes across all SMC clusters, and in a Marfan model disease-associated responses were comparable between clusters. Many embryologic markers of murine aortic SMCs were not detected in adult human aorta at all (Ren 2024, PMID 39697172). Lineage therefore appears to set spatial context and possibly baseline TGF-β responsiveness, but does not by itself explain differential vulnerability to TGF-β pathway disruption.

Regional heterogeneity also exists at scales below lineage: within a single aneurysm, ECM composition and mechanical properties vary by quadrant and by curvature, and co-vary with local haemodynamics (PMID 26293758; Bollache 2018, PMID 30060930; Salmasi 2022, PMID 35894942). See anatomy and classification and bicuspid aortopathy.

8. Integrating the mechanisms

Four historically separate explanations — TGF-β activation, contractile apparatus defects, ECM defects, and mechanosensing failure — have been proposed to converge, though whether they truly converge on a common final pathway remains debated (Yamashiro 2017, PMID 28943527). The mechanobiological framing treats aortic homeostasis as a set of negative feedback loops in which intramural cells sense their chemomechanical environment and remodel the ECM to hold stress and stiffness near set points; disease is the replacement of those loops by biomechanical and biochemical positive feedback (Humphrey 2021, PMID 34255994; Humphrey 2015, PMID 25858068). The strongest empirical support comes from comparative biomechanics: across 10 murine models, reduced elastic energy storage or distensibility did not predict aneurysm formation; what characterised aneurysm-prone aortas was inability of intramural cells to maintain or restore intrinsic circumferential material stiffness despite normal or subnormal wall stress (Bellini 2017, PMID 28490606). Additional candidate contributors under active investigation include mitochondrial dysfunction and mtDNA heteroplasmy (Suslov 2021, PMID 34947926) and the omics-scale gene expression changes catalogued in omics and emerging science.

Open questions

  • Is elevated TGF-β signalling in aneurysmal aorta causal, compensatory, or epiphenomenal? Habashi showed prevention of aneurysm by TGF-β antagonism (PMID 16601194), yet SMC-specific receptor deletion worsens disease (PMID 24401272) and signalling is unaltered in young Marfan mouse SMCs (PMID 28119285). No experiment has yet separated the cell type, compartment and time window in which TGF-β is harmful from those in which it is protective.
  • Which cell compartment is the primary driver — medial SMC or adventitial fibroblast — and does it differ by genotype? Marfan mice show a discrete modSMC cluster (PMID 32698686), whereas Loeys–Dietz mice and human LDS tissue show adventitial fibroblast activation without a modSMC cluster (PMID 40109260). Whether this reflects a genuine biological split or differences in model and sampling is unresolved.
  • Does embryologic lineage confer differential vulnerability, or only differential location? Disease localises to SHF-derived outer media (PMID 35143327), yet TGF-β receptor deletion perturbs cardiac- and neural-crest-derived SMC clusters equivalently, and murine lineage markers are largely undetectable in adult human aorta (PMID 39697172).
  • What causes mucoid ECM accumulation, and is it a cause or a consequence of dissection? MEMA is the most TAAD-specific histologic feature and has a proposed mechanical role in nucleating delamination (PMID 23018968), but no study has prospectively shown GAG pooling preceding intramural tear in humans.
  • Is medial SMC loss in human TAA apoptotic? Multiple death programmes are implicated mechanistically (PMID 34597613), yet a detailed ultrastructural/ISEL study found no apoptosis in human ascending aneurysm media (PMID 11567232) and consensus histopathology attributes SMC nuclei loss chiefly to ageing (PMID 28646716).
  • Why do MMP profiles differ so sharply between Marfan and non-syndromic ascending aneurysm — with MMP-2 reduced in Marfan and most MMPs reduced in non-syndromic tissue relative to non-aneurysmal aorta (PMID 16820601) — and does this mean anti-proteolytic therapy would need to be genotype-stratified?

References

  1. Halushka MK, Angelini A, Bartoloni G, et al. Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association For European Cardiovascular Pathology: II. Noninflammatory degenerative diseases - nomenclature and diagnostic criteria. Cardiovasc Pathol. 2016;25:247-257. PMID 27031798
  2. Stone JR, Bruneval P, Angelini A, et al. Consensus statement on surgical pathology of the aorta ... I. Inflammatory diseases. Cardiovasc Pathol. 2015;24:267-78. PMID 26051917
  3. Waters KM, Rooper LM, Guajardo A, Halushka MK. Histopathologic differences partially distinguish syndromic aortic diseases. Cardiovasc Pathol. 2017;30:6-11. PMID 28646716
  4. Karimi A, Milewicz DM. Structure of the Elastin-Contractile Units in the Thoracic Aorta and How Genes That Cause Thoracic Aortic Aneurysms and Dissections Disrupt This Structure. Can J Cardiol. 2015;32:26-34. PMID 26724508
  5. Rodrigues Bento J, Meester J, Luyckx I, et al. The Genetics and Typical Traits of Thoracic Aortic Aneurysm and Dissection. Annu Rev Genomics Hum Genet. 2022;23:223-253. PMID 36044906
  6. Pereira L, Andrikopoulos K, Tian J, et al. Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. Nat Genet. 1997;17:218-22. PMID 9326947
  7. Pereira L, Lee SY, Gayraud B, et al. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci U S A. 1999;96:3819-23. PMID 10097121
  8. Ramirez F, Gayraud B, Pereira L. Marfan syndrome: new clues to genotype-phenotype correlations. Ann Med. 1999;31:202-7. PMID 10442675
  9. Judge DP, Biery NJ, Keene DR, et al. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest. 2004;114:172-81. PMID 15254584
  10. Chen M, Cavinato C, Hansen J, et al. FN (Fibronectin)-Integrin α5 Signaling Promotes Thoracic Aortic Aneurysm in a Mouse Model of Marfan Syndrome. Arterioscler Thromb Vasc Biol. 2023;43:e132-e150. PMID 36994727
  11. Lesauskaite V, Tanganelli P, Sassi C, et al. Smooth muscle cells of the media in the dilatative pathology of ascending thoracic aorta: morphology, immunoreactivity for osteopontin, matrix metalloproteinases, and their inhibitors. Hum Pathol. 2001;32:1003-11. PMID 11567232
  12. Ikonomidis JS, Jones JA, Barbour JR, et al. Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms of patients with Marfan syndrome. Circulation. 2006;114(1 Suppl):I365-70. PMID 16820601
  13. Huusko T, Salonurmi T, Taskinen P, et al. Elevated messenger RNA expression and plasma protein levels of osteopontin and matrix metalloproteinase types 2 and 9 in patients with ascending aortic aneurysms. J Thorac Cardiovasc Surg. 2012;145:1117-1123. PMID 22571802
  14. Guzzardi DG, Barker AJ, van Ooij P, et al. Valve-Related Hemodynamics Mediate Human Bicuspid Aortopathy: Insights From Wall Shear Stress Mapping. J Am Coll Cardiol. 2015;66:892-900. PMID 26293758
  15. Mäki JM, Räsänen J, Tikkanen H, et al. Inactivation of the lysyl oxidase gene Lox leads to aortic aneurysms, cardiovascular dysfunction, and perinatal death in mice. Circulation. 2002;106:2503-9. PMID 12417550
  16. LeMaire SA, Zhang L, Zhang NS, et al. Ciprofloxacin accelerates aortic enlargement and promotes dissection and rupture in Marfan mice. J Thorac Cardiovasc Surg. 2020;163:e215-e226. PMID 34586071
  17. Pedroza AJ, Tashima Y, Shad R, et al. Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm. Arterioscler Thromb Vasc Biol. 2020;40:2195-2211. PMID 32698686
  18. Dalal AR, Pedroza AJ, Kim JL, et al. Chemokine (C-C Motif) Ligand 2 Expressing Adventitial Fibroblast Expansion During Loeys-Dietz Syndrome Aortic Aneurysm Formation. Arterioscler Thromb Vasc Biol. 2025;45:722-742. PMID 40109260
  19. Chakraborty A, Li Y, Zhang C, et al. Programmed cell death in aortic aneurysm and dissection: A potential therapeutic target. J Mol Cell Cardiol. 2021;163:67-80. PMID 34597613
  20. Guo DC, Pannu H, Tran-Fadulu V, et al. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet. 2007;39:1488-93. PMID 17994018
  21. Humphrey JD, Milewicz DM, Tellides G, Schwartz MA. Cell biology. Dysfunctional mechanosensing in aneurysms. Science. 2014;344:477-9. PMID 24786066
  22. Humphrey JD, Schwartz MA, Tellides G, Milewicz DM. Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections. Circ Res. 2015;116:1448-61. PMID 25858068
  23. Neptune ER, Frischmeyer PA, Arking DE, et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003;33:407-11. PMID 12598898
  24. Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006;312:117-21. PMID 16601194
  25. Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006;355:788-98. PMID 16928994
  26. Li W, Li Q, Jiao Y, et al. Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis. J Clin Invest. 2014;124:755-67. PMID 24401272
  27. Wei H, Hu JH, Angelov SN, et al. Aortopathy in a Mouse Model of Marfan Syndrome Is Not Mediated by Altered Transforming Growth Factor β Signaling. J Am Heart Assoc. 2017;6:e004968. PMID 28119285
  28. Angelov SN, Hu JH, Wei H, et al. TGF-β (Transforming Growth Factor-β) Signaling Protects the Thoracic and Abdominal Aorta From Angiotensin II-Induced Pathology by Distinct Mechanisms. Arterioscler Thromb Vasc Biol. 2017;37:2102-2113. PMID 28729364
  29. Humphrey JD. Possible mechanical roles of glycosaminoglycans in thoracic aortic dissection and associations with dysregulated transforming growth factor-β. J Vasc Res. 2012;50:1-10. PMID 23018968
  30. Lacro RV, Dietz HC, Sleeper LA, et al. Atenolol versus losartan in children and young adults with Marfan's syndrome. N Engl J Med. 2014;371:2061-71. PMID 25405392
  31. Kang YN, Chi SC, Wu MH, Chiu HH. The effects of losartan versus beta-blockers on cardiovascular protection in marfan syndrome: A systematic review and meta-analysis. J Formos Med Assoc. 2019;119:182-190. PMID 31003918
  32. Humphrey JD, Milewicz DM. The aorta in Marfan syndrome: from molecular mechanisms to mechanobiological dysfunction. Cardiovasc Res. 2026;122:1427-1442. PMID 42140666
  33. He R, Guo DC, Sun W, et al. Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms. J Thorac Cardiovasc Surg. 2008;136:922-9. PMID 18954631
  34. Phillips EH, Yrineo AA, Schroeder HD, et al. Morphological and Biomechanical Differences in the Elastase and AngII apoE(-/-) Rodent Models of Abdominal Aortic Aneurysms. Biomed Res Int. 2015;2015:413189. PMID 26064906
  35. Humphrey JD, Schwartz MA. Vascular Mechanobiology: Homeostasis, Adaptation, and Disease. Annu Rev Biomed Eng. 2021;23:1-27. PMID 34255994
  36. Sawada H, Rateri DL, Moorleghen JJ, Majesky MW, Daugherty A. Smooth Muscle Cells Derived From Second Heart Field and Cardiac Neural Crest Reside in Spatially Distinct Domains in the Media of the Ascending Aorta-Brief Report. Arterioscler Thromb Vasc Biol. 2017;37:1722-1726. PMID 28663257
  37. Sawada H, Katsumata Y, Higashi H, et al. Second Heart Field-Derived Cells Contribute to Angiotensin II-Mediated Ascending Aortopathies. Circulation. 2022;145:987-1001. PMID 35143327
  38. Ren P, Jiang B, Hassab AHM, et al. Heterogeneous Cardiac-Derived and Neural Crest-Derived Aortic Smooth Muscle Cells Exhibit Similar Transcriptional Changes After TGFβ Signaling Disruption. Arterioscler Thromb Vasc Biol. 2024;45:260-276. PMID 39697172
  39. Bollache E, Guzzardi DG, Sattari S, et al. Aortic valve-mediated wall shear stress is heterogeneous and predicts regional aortic elastic fiber thinning in bicuspid aortic valve-associated aortopathy. J Thorac Cardiovasc Surg. 2018;156:2112-2120. PMID 30060930
  40. Salmasi MY, Sasidharan S, Frattolin J, et al. Regional variation in biomechanical properties of ascending thoracic aortic aneurysms. Eur J Cardiothorac Surg. 2022;62:ezac392. PMID 35894942
  41. Yamashiro Y, Yanagisawa H. Crossing Bridges between Extra- and Intra-Cellular Events in Thoracic Aortic Aneurysms. J Atheroscler Thromb. 2017;25:99-110. PMID 28943527
  42. Bellini C, Bersi MR, Caulk AW, et al. Comparison of 10 murine models reveals a distinct biomechanical phenotype in thoracic aortic aneurysms. J R Soc Interface. 2017;14:20161036. PMID 28490606
  43. Suslov AV, Afanasyev MA, Degtyarev PA, et al. Molecular Pathogenesis and the Possible Role of Mitochondrial Heteroplasmy in Thoracic Aortic Aneurysm. Life (Basel). 2021;11:1395. PMID 34947926