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Animal Models of Thoracic Aortic Aneurysm

TL;DR — Nearly all TAA mechanism comes from mice. The workhorses are the two Marfan lines — Fbn1^C1041G/+ (mild, haploinsufficiency-driven) and Fbn1^mgR/mgR (severe, hypomorphic, with inflammatory elastolysis) — plus conditional Tgfbr1/2 deletions, contractile-protein mutants (Acta2^−/−, Myh11^R247C/R247C), cross-linking models (Lox^−/−, BAPN lathyrism), and chemical induction with angiotensin II. Each captures a slice of human disease and none captures all of it. The defining cautionary tale is losartan: it prevented aortic aneurysm in Fbn1^C1039G/+ mice (Habashi 2006, PMID 16601194) but did not outperform atenolol in 608 children and young adults with Marfan syndrome (Lacro 2014, PMID 25405392), and a meta-analysis of 8 trials in 1381 patients found no significant difference in aortic growth or events (Kang 2019, PMID 31003918). Comparative biaxial testing across 10 murine models found that no measure of reduced mechanical function predicted aneurysm — only failure to maintain circumferential material stiffness did (Bellini 2017, PMID 28490606). Mouse aortas mostly dilate rather than spontaneously dissect at human-like sites and ages; a 2025 consensus recommendations paper exists precisely because model choice, phenotype detection and reporting have been inconsistent enough to distort the literature (Daugherty 2025, PMID 40079138).

1. Mouse model table

Model Genetic / chemical lesion Phenotype Key uses Citation
Fbn1^mgΔ (targeted Fbn1) Gene-targeted fibrillin-1 disruption Vascular Marfan phenotype; microfibrils shown to serve tissue homeostasis more than elastic matrix assembly; adventitial microfibrillar failure to sustain haemodynamic stress with medial elastic disruption secondary Established that fibrillin-1 is homeostatic, not merely structural Pereira 1997, PMID 9326947
Fbn1^mgR/mgR Hypomorphic — fibrillin-1 underexpression Progressive severe MFS; dissecting aneurysm with medial calcification, inflammatory-fibroproliferative response, inflammation-mediated elastolysis; threshold effect of microfibril level/integrity on wall collapse Severe/lethal aneurysm progression; drug studies where survival is the endpoint Pereira 1999, PMID 10097121; Ramirez 1999, PMID 10442675
Fbn1^C1039G/+ (a.k.a. C1041G/+) Heterozygous missense knock-in (cysteine substitution) Impaired microfibrillar deposition, skeletal deformity, progressive deterioration of aortic wall architecture; rescued by a wild-type FBN1 transgene → haploinsufficiency, not dominant-negative The standard mild MFS line; substrate for the losartan experiment and for scRNA-seq of SMC modulation Judge 2004, PMID 15254584
Fbn1 mouse + losartan Pharmacologic AT1 blockade Aortic aneurysm prevented; a TGF-β–neutralising antibody also prevented it; partial rescue of alveolar septation Origin of the ARB hypothesis in aortopathy Habashi 2006, PMID 16601194
Fbn1-deficient mouse (lung/TGF-β) Fibrillin-1 deficiency Impaired distal alveolar septation, later emphysema; marked dysregulation of TGF-β activation/signalling with apoptosis; rescued by perinatal TGF-β antagonism Established matrix sequestration of TGF-β as a disease mechanism Neptune 2003, PMID 12598898
SMC-specific Tgfbr2^−/− (postweanling) Conditional Tgfbr2 deletion in smooth muscle Thoracic aorta rapidly thickens, dilates and dissects; ↓Smad, ↑MAPK; perturbed medial contractile apparatus + adventitial growth-factor production (maladaptive paracrine crosstalk); rapamycin prevents dissection; accelerates aneurysm on MFS background Demonstrates that basal TGF-β signalling is protective postnatally Li 2014, PMID 24401272
Fbn1^C1041G/+ × SMC Tgfbr2^−/− Combined Aortopathy develops without detectable alteration in SMC TGF-β signalling in young mice; superimposed receptor deletion exacerbates dilation and medial disruption Central evidence against the simple "excess TGF-β" model Wei 2017, PMID 28119285
Systemic TGF-β neutralisation vs SMC-specific loss + AngII Antibody vs conditional deletion Systemic blockade significantly ↑abdominal aneurysm prevalence (severity, adventitial thickening and macrophages trended up without reaching significance); SMC-specific loss significantly ↑thoracic pathology (intramural haematoma, medial thinning) Shows territorially distinct protective mechanisms Angelov 2017, PMID 28729364
Tgfbr1-based Loeys–Dietz models TGFBR1/2, SMAD2/3, TGFB2/3 pathway lesions Aggressive aortopathy; adventitial fibroblast pro-inflammatory conversion (Ccl2) rather than a discrete modulated-SMC cluster; ~6-fold ↑ aortic wall macrophage content Mechanistically separates LDS from MFS Dalal 2025, PMID 40109260; reviewed Bousbaa 2026, PMID 42380922
SHF-lineage conditional deletions (Lrp1, Tgfbr2) Mef2c-Cre driven SHF-Lrp1 deletion augments AngII-induced ascending aneurysm and rupture; SHF-Tgfbr2 deletion lethal at E12.5 with dilated outflow tract and retroperitoneal haemorrhage Tests embryologic-lineage contribution to segment specificity Sawada 2022, PMID 35143327
Acta2^−/− SM α-actin null Cardiovascular system forms normally; viable and fertile; compensatory skeletal α-actin activation in aorta; highly compromised vascular contractility, tone and blood flow but no severe spontaneous aortic phenotype Isolates the contribution of contractile force to wall integrity Schildmeyer 2000, PMID 11053242
Myh11^R247C/R247C Knock-in of a human FTAAD SM-MHC variant Near-normal biaxial biomechanics under normotension and near-normal adaptation to induced hypertension — yet >20% intramural delaminations or premature death under hypertension, with localised mucoid pools resembling human TAAD histology Demonstrates a "second-hit" model: contractile mutation + haemodynamic stress Bellini 2015, PMID 25433566; human genetics reviewed Atash 2026, PMID 41891259
Lox^−/− Lysyl oxidase knockout Death at end of gestation or as neonates; large aortic aneurysms; hazy unruffled then highly fragmented elastic lamellae; discontinuous SMC layers; thicker wall, smaller lumen; abnormal Doppler impedance Establishes collagen/elastin cross-linking as essential to wall integrity Mäki 2002, PMID 12417550
BAPN (lathyrism) β-aminopropionitrile, irreversible LOX inhibitor, in drinking water Dose-dependent dissection in C57BL/6J: dissection incidence 0/10, 3/10, 5/10, 9/10 at 0, 0.2, 0.4, 0.8 g·kg⁻¹·d⁻¹; ruptured-AD mortality 0%, 20%, 40%, 70%. Thoracic aortic diameter 1.38 ± 0.19 mm (control) → 2.87 ± 0.57 mm at 0.8 g·kg⁻¹·d⁻¹; blood-filled false lumen and elastic fibre fragmentation Wild-type background model of acute dissection; drug and mechanism studies Gao 2018, PMID 29495238
BAPN + angiotensin II (rat) 0.06–0.1% BAPN in water, then AngII 1 µg/kg/min osmotic minipump Dissection in 70% (0.08% BAPN) and 75% (0.1%); rupture rates differed significantly between doses (55% vs 20%, p=0.022); authors favoured 0.08% as high-incidence/lower-mortality; MRI showed double lumen and intimal tears Rat model with imaging-verifiable dissection Lv 2020, PMID 33357159
Angiotensin II in ApoE^−/− Osmotic minipump AngII on hyperlipidaemic background Predominantly suprarenal abdominal; non-lethal haemorrhagic lesions are largely pseudoaneurysms (contained rupture with subadventitial haematoma) rather than true dissections; medial thickening from SMC hypertrophy and matricellular protein accumulation. mTOR inhibition (rapamycin) prevented rupture but promoted dissection Widely used but frequently mis-labelled; a caution for reinterpreting the AngII literature He 2022, PMID 35132962
Elastase perfusion Intraluminal pancreatic elastase, rat/mouse infrarenal aorta Abdominal aneurysm with marked changes in vessel strain and blood flow velocity; elastin and collagen levels and spatial distribution similarly affected as in AngII-ApoE^−/− AAA model — not a TAA model. Used comparatively; also used as an acute elastic-fibre-degradation control in TAA biomechanics Phillips 2015, PMID 26064906; used as acute-elastase arm in Bellini 2017, PMID 28490606
Fbn1 mouse + ciprofloxacin Fluoroquinolone exposure on MFS background Accelerated aortic enlargement (p=0.01); dissection 25% → 47% (p=0.03); rupture 5% → 25% (p=0.005); more elastic fibre fragmentation, MMP expression and apoptosis; LOX suppression proposed Toxicology model directly informing a clinical drug caution LeMaire 2020, PMID 34586071
mgR × integrin α5/2 chimera Integrin α5 cytoplasmic tail replaced with α2 Greatly prolonged survival; improved elastic fibre integrity, mechanical properties, SMC density and contractile gene expression; NF-κB activation reduced Tests fibronectin–integrin mechanosignalling as a therapeutic node Chen 2023, PMID 36994727

2. What each class recapitulates — and what it does not

Fibrillin-1 models. These reproduce aortic root/ascending dilatation, elastic fibre fragmentation and (in mgR) frank dissection and death, and they map onto human genetics well: the C1039G line established haploinsufficiency as the operative mechanism, since a wild-type transgene rescues the aorta (PMID 15254584), and the mgR allelic series established a threshold model in which severity scales with the level and integrity of microfibrils (PMID 10097121). They do not reproduce the human clinical trajectory of decades-long slow growth punctuated by acute type A dissection in adulthood, and the mgR inflammatory-elastolytic phenotype is more florid than typical human Marfan histology (PMID 10097121; contrast human histopathology, PMID 28646716).

TGF-β pathway models. Conditional receptor deletion produces aortopathy, which is exactly the opposite of what the excess-TGF-β model predicts (PMID 24401272; PMID 28119285; PMID 28729364). This is a strength — the models falsified a hypothesis — but it also means "TGF-β model" is not a single thing: outcome depends on cell type targeted, timing of deletion, and territory examined. Loeys–Dietz mouse models further diverge from Marfan mechanistically, with adventitial fibroblasts rather than SMCs as the dominant modulating compartment (PMID 40109260; PMID 42380922).

Contractile-protein models. These are the clearest illustration of the gap between human genetics and mouse phenotype. ACTA2 missense mutations cause ~14% of inherited human ascending TAAD (Guo 2007, PMID 17994018), yet Acta2^−/− mice form a normal cardiovascular system, survive, feed and reproduce, and compensate by activating skeletal α-actin — showing only impaired contractility, tone and blood flow (PMID 11053242). Similarly Myh11^R247C/R247C mice show near-normal biomechanics at normotension; the vascular phenotype only emerges as intramural delamination and premature death when hypertension is superimposed (PMID 25433566). The interpretation is that contractile mutations create vulnerability requiring an epigenetic/haemodynamic second hit rather than causing disease autonomously — and that focal, not global, changes (including mucoid pooling) are the ones to look for (PMID 25433566).

Cross-linking models. Lox^−/− is perinatally lethal and therefore useless for adult aneurysm progression studies, but definitive on the necessity of cross-linking (PMID 12417550). BAPN is its tractable pharmacologic surrogate: it acts on a wild-type genetic background, produces dose-titratable dissection incidence and mortality, and generates blood-filled false lumens with elastic fibre fragmentation (PMID 29495238). Its weakness is aetiologic realism — human TAA is not a lathyrism — and the frequent combination with AngII stacks two non-physiologic insults (PMID 33357159).

Chemical/haemodynamic induction. Angiotensin II infusion is the most-used inducible model and the most frequently misdescribed. Careful phenotyping showed that non-lethal haemorrhagic lesions in AngII-infused ApoE^−/− mice are pseudoaneurysms — contained rupture with subadventitial haematoma — rather than classical dissections, and that mTOR inhibition dissociates the two failure modes (preventing rupture while promoting dissection). The authors explicitly advise reinterpreting prior AngII mechanistic studies as clinically relevant to pseudoaneurysm (PMID 35132962). Elastase perfusion is an abdominal model and should not be presented as a TAA model, though it is legitimately used as an acute elastic-fibre-degradation comparator (PMID 26064906; PMID 28490606).

3. Comparative biomechanical phenotyping

The single most useful cross-model study measured biaxial mechanical properties of the ascending aorta across ten murine groups — wild-type controls, acute elastase treatment, and eight genetic models affecting extracellular matrix proteins, transmembrane receptors, cytoskeletal proteins or intracellular signalling molecules. Its conclusion inverts the intuitive model (Bellini 2017, PMID 28490606):

  • Reduced mechanical function — decreased elastic energy storage or reduced distensibility — did not predispose to aneurysm.
  • Aneurysm-prone aortas showed normal or lower than normal circumferential and axial wall stresses.
  • What characterised them was inability of intramural cells to maintain or restore intrinsic circumferential material stiffness.

This is consistent with an underlying defect in mechanosensing or mechanoregulation of the ECM, which normally endows the wall with both appropriate compliance and sufficient strength — the framework developed in pathophysiology and quantified in hemodynamics and biomechanics.

4. The translational gap

Step Mouse Human
TGF-β dysregulation identified in fibrillin-1 deficiency Yes; TGF-β antagonism rescues lung phenotype (PMID 12598898) Consistent with increased TGF-β markers in Marfan and LDS tissue (PMID 16820601; PMID 16928994)
Losartan prevents aneurysm Yes, in Fbn1^C1039G/+ (PMID 16601194); ameliorated vascular disease in Fbn1^mgR/mgR (PMID 20871099) No superiority. 608 patients aged 6 months–25 years, aortic-root z-score slope −0.139 ± 0.013 (atenolol) vs −0.107 ± 0.013 (losartan) SD units/yr, p=0.08; no difference in 3-year rates of aortic surgery, dissection or death (PMID 25405392)
Confirmatory meta-analysis — 8 randomised trials, 1381 patients: no significant difference in aortic root diameter change (SMD 0.04, 95% CI −0.11–0.19, p=0.63), dissection, surgery or death (PMID 31003918)
Mechanistic re-examination SMC-specific TGF-β receptor deletion worsens aortopathy (PMID 24401272; PMID 28119285); TGF-β is protective in both territories by distinct routes (PMID 28729364) —

Several non-exclusive explanations for the gap are on the table, and they are worth separating because they imply different fixes:

  1. The target was misidentified. If basal TGF-β signalling is protective and the observed excess is compensatory, then AT1 blockade was never acting on the causal node. The mouse rescue may have operated through blood-pressure and haemodynamic-unloading effects that atenolol reproduces.
  2. Model severity mismatch. Mouse experiments start treatment before or at disease onset in a genetically uniform, short-lived animal; the trial enrolled children with established aortic-root z-scores > 3.0 and ran 3 years (PMID 25405392).
  3. Endpoint mismatch. Mouse studies read out aortic diameter, elastic fibre integrity and survival over weeks; the trial's primary endpoint was rate of change in a body-surface-area-indexed z-score over 3 years — and both arms showed decreasing z-score, i.e. the comparator was active (PMID 25405392).
  4. Species biomechanics. Mouse heart rate (~500–600 bpm), aortic dimensions and wall composition differ by orders of magnitude from human; cyclic loading history over a mouse lifetime is not comparable, and mouse aortas rarely undergo the spontaneous adult type A dissection that dominates human mortality.

The current framing is that the Marfan aorta has hundreds of differentially expressed genes, many cell-type-specific, that must be sorted into protective compensations, pathologic consequences and neutral changes before a therapeutic target can be chosen with confidence — with data-driven computational models proposed as the integrating tool (Humphrey 2026, PMID 42140666). See medical therapy for the clinical-trial layer and clinical trials landscape for what is currently being tested.

5. Large-animal and non-mammalian models

Rodents dominate, but the limitation is recognised. A 2024 review of TAA animal models covers recent development of porcine models — valuable because a large mammal permits testing of therapeutic devices and interventional strategies at clinically relevant scale — and zebrafish models, which enable large-scale small-molecule suppressor screening in microwells (Wang 2024, PMID 38255976).

Three primary porcine protocols anchor that literature. All target the descending thoracic aorta and all produce dilatation within weeks:

Protocol Method Result Citation
Collagenase + CaCl₂, Yorkshire pig Intra-adventitial collagenase (5 mL, 0.35 mg/mL) plus periadventitial crystalline CaCl₂ (0.5 g); n=7 vs 6 sham; harvest at 3 weeks Aortic luminal area ↑38 ± 13% (p=0.018 vs control); elastic lamellar degradation, decreased collagen; ↑MMP-3, -8, -9, -12 and ↓TIMP-1, -4 Eckhouse 2013, PMID 24030405
Intra-adventitial elastase, Wuzhishan minipig Elastase 5 mL at 20 mg/mL injected circumferentially over a 2-cm segment beginning 0.5 cm from the left subclavian; n=12 vs 6 saline controls TAA in 12/12 elastase animals, 0/6 controls; diameter 15.42 ± 0.43 → 24.53 ± 1.41 mm at 3 weeks (p<0.0001, controls unchanged p=0.52); SMC loss, elastic fibre degradation, ↑MMP-2 and MMP-9 Tian 2017, PMID 28479097
Endovascular retrievable drug-infusion stent graft, Yorkshire pig Percutaneous femoral access; stent isolates a thoracic aortic segment for 30-min exposure to elastase + collagenase + trypsin; no thoracotomy; n=5 Aneurysm in 5/5 within 1 week, 1.4 ± 0.1 → 2.9 ± 0.7 cm (p=0.002), confined to the treated segment and persisting to 4 weeks; elastin and collagen loss, ↑MMP activity and proinflammatory cytokines Kenawy 2024, PMID 39188992

An ovine analogue exists for dissection rather than aneurysm: acute type B dissection created by purely endovascular means in 17 sheep with 82% technical success, false-lumen systolic pressure lower than true-lumen (58 ± 5 vs 79 ± 3 mmHg, p<0.001), built as a testbed for endovascular fenestration devices (El Batti 2018, PMID 30005965).

Note the limits. All three porcine protocols are enzymatic/chemical injury to the descending aorta in young, genetically normal pigs; none reproduces root or ascending aortopathy, none is genetic, and none has been followed long enough to report spontaneous dissection or rupture rates. Their demonstrated value is device testing, longitudinal imaging and interventional training at clinically relevant scale — not aetiologic fidelity.

6. Key limitations and reporting standards

Limitation Detail
Mice rarely dissect like humans Genetic models predominantly dilate; frank dissection usually requires a second insult (hypertension in Myh11^R247C, PMID 25433566) or chemical induction (BAPN, PMID 29495238)
Lesion misclassification AngII-ApoE^−/− haemorrhagic lesions are largely pseudoaneurysms, not dissections (PMID 35132962)
Territory mismatch Elastase and AngII-ApoE^−/− produce abdominal disease (PMID 26064906); human TAA biology is thoracic and largely non-atherosclerotic
Haemodynamic mismatch Mouse heart rate, pressure waveform and aortic geometry differ radically; valve-mediated eccentric jets central to human BAV aortopathy have no straightforward murine equivalent (PMID 26293758)
Compensation obscures phenotype Acta2^−/− mice activate skeletal α-actin, blunting the phenotype relative to human ACTA2 disease (PMID 11053242 vs PMID 17994018)
Lineage markers do not transfer Many embryologic markers of murine aortic SMCs are not detected in adult human aorta (Ren 2024, PMID 39697172)
Methodological heterogeneity A 2025 consensus paper gives recommendations on model selection, standardised detection and measurement of aortic disease, interpretation of diseased tissue characteristics, and rigour/transparency reporting — written because the field's inconsistency has been distorting conclusions (Daugherty 2025, PMID 40079138)

Practical implications of the recommendations paper for anyone reading or designing a mouse aortopathy study: state sex, age, background strain and Cre driver; distinguish dilatation, dissection, intramural haematoma, pseudoaneurysm and rupture explicitly; specify whether diameters are in vivo (ultrasound/MRI) or ex vivo and whether measured at systole or unloaded; and report deaths and their causes rather than only survivors (PMID 40079138).

Open questions

  • Does any mouse model recapitulate spontaneous adult type A dissection at human-like frequency without a second insult? Genetic models dilate; dissection needs superimposed hypertension (PMID 25433566) or LOX inhibition (PMID 29495238), and the most common inducible model produces pseudoaneurysm rather than dissection (PMID 35132962).
  • Why did losartan's mouse efficacy not transfer? The mouse rescue is robust (PMID 16601194; PMID 20871099) and the human null is robust (PMID 25405392; PMID 31003918); no experiment has yet identified which of target misidentification, timing, endpoint or species mechanics is responsible.
  • Is the protective role of SMC TGF-β signalling a mouse-specific artefact of conditional-deletion timing? Deletion in postweanling mice causes dissection within days (PMID 24401272) — a time course with no human analogue — yet the same manipulation exacerbates a Marfan background (PMID 28119285). Whether graded, adult-onset partial loss behaves the same way is untested.
  • Do contractile-protein mutants require haemodynamic second hits in humans too? Myh11^R247C/R247C mice are near-normal until hypertension is induced (PMID 25433566), and human MYH11 disease shows reduced penetrance and variable expression with unknown gene–environment interactions (PMID 41891259) — but no human cohort has directly tested blood-pressure exposure as the modifier.
  • Should the AngII literature be re-read? If a substantial fraction of "AngII-induced dissection" lesions are pseudoaneurysms (PMID 35132962), the mechanistic conclusions drawn from two decades of that model may apply to a different failure mode than intended.
  • Can large-animal models close the biomechanical gap? Porcine models are proposed for device and interventional testing and zebrafish for suppressor screening (PMID 38255976), but neither has yet been shown to predict human therapeutic response better than mice. All three published porcine protocols are enzymatic injury to the descending aorta (PMID 24030405; PMID 28479097; PMID 39188992); no large-animal model of root or ascending aortopathy — the segment that dominates human disease — has been reported.

References

  1. 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
  2. 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
  3. Ramirez F, Gayraud B, Pereira L. Marfan syndrome: new clues to genotype-phenotype correlations. Ann Med. 1999;31:202-7. PMID 10442675
  4. 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
  5. 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
  6. 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
  7. Nistala H, Lee-Arteaga S, Carta L, et al. Differential effects of alendronate and losartan therapy on osteopenia and aortic aneurysm in mice with severe Marfan syndrome. Hum Mol Genet. 2010;19:4790-8. PMID 20871099
  8. 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
  9. 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
  10. 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
  11. 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
  12. Bousbaa A, Fedoryshchenko I, Luyckx I, Loeys B, Verstraeten A. Preclinical modeling of Loeys-Dietz syndrome: insights into mechanisms and therapy. Orphanet J Rare Dis. 2026. PMID 42380922
  13. 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
  14. Schildmeyer LA, Braun R, Taffet G, et al. Impaired vascular contractility and blood pressure homeostasis in the smooth muscle alpha-actin null mouse. FASEB J. 2000;14:2213-20. PMID 11053242
  15. 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
  16. Bellini C, Wang S, Milewicz DM, Humphrey JD. Myh11(R247C/R247C) mutations increase thoracic aorta vulnerability to intramural damage despite a general biomechanical adaptivity. J Biomech. 2015;48:113-21. PMID 25433566
  17. Atash A, Mees BME, Cramer MJ, et al. MYH11 variants in thoracic aortic aneurysm pathophysiology: From bench to bedside. Eur J Clin Invest. 2026;56:e70196. PMID 41891259
  18. 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
  19. Gao YX, Liu YT, Zhang YY, et al. [Establishment of β-aminopropionitrile-induced aortic dissection model in C57Bl/6J mice]. Zhonghua Xin Xue Guan Bing Za Zhi. 2018;46:137-142. PMID 29495238
  20. Lv X, Hu Y, Chen X, et al. Establishment and effect evaluation of an aortic dissection model induced by different doses of β-aminopropionitrile in rats. Vascular. 2020;29:832-840. PMID 33357159
  21. He C, Jiang B, Wang M, et al. mTOR inhibition prevents angiotensin II-induced aortic rupture and pseudoaneurysm but promotes dissection in Apoe-deficient mice. JCI Insight. 2022;7:e155815. PMID 35132962
  22. 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
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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
  28. Humphrey JD, Milewicz DM. The aorta in Marfan syndrome: from molecular mechanisms to mechanobiological dysfunction. Cardiovasc Res. 2026;122:1427-1442. PMID 42140666
  29. Wang Y, Panicker IS, Anesi J, et al. Animal Models, Pathogenesis, and Potential Treatment of Thoracic Aortic Aneurysm. Int J Mol Sci. 2024;25:901. PMID 38255976
  30. Daugherty A, Milewicz DM, Dichek DA, et al. Recommendations for Design, Execution, and Reporting of Studies on Experimental Thoracic Aortopathy in Preclinical Models. Arterioscler Thromb Vasc Biol. 2025;45:609-631. PMID 40079138
  31. 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
  32. Waters KM, Rooper LM, Guajardo A, Halushka MK. Histopathologic differences partially distinguish syndromic aortic diseases. Cardiovasc Pathol. 2017;30:6-11. PMID 28646716
  33. 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
  34. 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
  35. 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
  36. Eckhouse SR, Logdon CB, Oelsen JM, et al. Reproducible porcine model of thoracic aortic aneurysm. Circulation. 2013;128(11 Suppl 1):S186-93. PMID 24030405
  37. Tian Y, Zhang W, Sun J, et al. A reproducible swine model of proximal descending thoracic aortic aneurysm created with intra-adventitial application of elastase. J Vasc Surg. 2017;67:300-308.e2. PMID 28479097
  38. Kenawy DM, Stafford JF, Amari F, et al. A porcine model of thoracic aortic aneurysms created with a retrievable drug infusion stent graft mirrors human aneurysm pathophysiology. JVS Vasc Sci. 2024;5:100212. PMID 39188992
  39. El Batti S, Ben Abdallah I, Dufetelle E, Julia P, Menasche P, Alsac JM. Experimental Evaluation of Endovascular Fenestration Scissors in an Ovine Model of Aortic Dissection. Eur J Vasc Endovasc Surg. 2018;56:373-380. PMID 30005965