1932

Abstract

Genetic predisposition and risk factors such as hypertension and smoking can instigate the development of thoracic aortic aneurysm (TAA), which can lead to highly lethal aortic wall dissection and/or rupture. Monogenic defects in multiple genes involved in the elastin-contractile unit and the TGFβ signaling pathway have been associated with TAA in recent years, along with several genetic modifiers and risk-conferring polymorphisms. Advances in omics technology have also provided significant insights into the processes behind aortic wall degeneration: inflammation, epigenetics, vascular smooth muscle phenotype change and depletion, reactive oxygen species generation, mitochondrial dysfunction, and angiotensin signaling dysregulation. These recent advances and findings might pave the way for a therapy that is capable of stopping and perhaps even reversing aneurysm progression.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-genom-111521-104455
2022-08-31
2024-12-04
Loading full text...

Full text loading...

/deliver/fulltext/genom/23/1/annurev-genom-111521-104455.html?itemId=/content/journals/10.1146/annurev-genom-111521-104455&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Achilleos A, Trainor PA. 2012. Neural crest stem cells: discovery, properties and potential for therapy. Cell Res 22:288–304
    [Google Scholar]
  2. 2.
    Angelov SN, Hu JH, Wei H, Airhart N, Shi M, Dichek DA. 2017. 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. 37:2102–13
    [Google Scholar]
  3. 3.
    Aoyama T, Tynan K, Dietz HC, Francke U, Furthmayr H. 1993. Missense mutations impair intracellular processing of fibrillin and microfibril assembly in Marfan syndrome. Hum. Mol. Genet. 2:2135–40
    [Google Scholar]
  4. 4.
    Ashvetiya T, Fan SX, Chen YJ, Williams CH, O'Connell JR et al. 2021. Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort. PLOS ONE 16:e0247287
    [Google Scholar]
  5. 5.
    Au DT, Ying Z, Hernández-Ochoa EO, Fondrie WE, Hampton B et al. 2018. LRP1 (low-density lipoprotein receptor–related protein 1) regulates smooth muscle contractility by modulating Ca2+ signaling and expression of cytoskeleton-related proteins. Arterioscler. Thromb. Vasc. Biol. 38:2651–64
    [Google Scholar]
  6. 6.
    Aubart M, Gazal S, Arnaud P, Benarroch L, Gross MS et al. 2018. Association of modifiers and other genetic factors explain Marfan syndrome clinical variability. Eur. J. Hum. Genet. 26:1759–72
    [Google Scholar]
  7. 7.
    Barbier M, Gross MS, Aubart M, Hanna N, Kessler K et al. 2014. MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections. Am. J. Hum. Genet. 95:736–43
    [Google Scholar]
  8. 8.
    Blakes AJM, Gaul E, Lam W, Shannon N, Knapp KM et al. 2021. Pathogenic variants causing ABL1 malformation syndrome cluster in a myristoyl-binding pocket and increase tyrosine kinase activity. Eur. J. Hum. Genet. 29:593–603
    [Google Scholar]
  9. 9.
    Boucher P, Li WP, Matz RL, Takayama Y, Auwerx J et al. 2007. LRP1 functions as an atheroprotective integrator of TGFβ and PDFG signals in the vascular wall: implications for Marfan syndrome. PLOS ONE 2:e448
    [Google Scholar]
  10. 10.
    Branchetti E, Poggio P, Sainger R, Shang E, Grau JB et al. 2013. Oxidative stress modulates vascular smooth muscle cell phenotype via CTGF in thoracic aortic aneurysm. Cardiovasc. Res. 100:316–24
    [Google Scholar]
  11. 11.
    Byers PH 2019. Vascular Ehlers-Danlos syndrome. GeneReviews MP Adam, HH Ardinger, RA Pagon, SE Wallace, LJH Bean, et al Seattle: Univ. Wash https://www.ncbi.nlm.nih.gov/books/NBK1494
    [Google Scholar]
  12. 12.
    Caescu CI, Hansen J, Crockett B, Xiao W, Arnaud P et al. 2021. Inhibition of HIPK2 alleviates thoracic aortic disease in mice with progressively severe Marfan syndrome. Arterioscler. Thromb. Vasc. Biol. 41:2483–93
    [Google Scholar]
  13. 13.
    Capuano A, Bucciotti F, Farwell KD, Tippin Davis B, Mroske C et al. 2016. Diagnostic exome sequencing identifies a novel gene, EMILIN1, associated with autosomal-dominant hereditary connective tissue disease. Hum. Mutat. 37:84–97
    [Google Scholar]
  14. 14.
    Chaudhry SS, Cain SA, Morgan A, Dallas SL, Shuttleworth CA, Kielty CM. 2007. Fibrillin-1 regulates the bioavailability of TGFβ1. J. Cell Biol. 176:355–67
    [Google Scholar]
  15. 15.
    Chen MH, Choudhury S, Hirata M, Khalsa S, Chang B, Walsh CA 2018. Thoracic aortic aneurysm in patients with loss of function Filamin A mutations: clinical characterization, genetics, and recommendations. Am. J. Med. Genet. A 176:337–50
    [Google Scholar]
  16. 16.
    Cheuk BL, Cheng SW. 2011. Differential expression of elastin assembly genes in patients with Stanford Type A aortic dissection using microarray analysis. J. Vasc. Surg. 53:1071–8.e2
    [Google Scholar]
  17. 17.
    Chung AW, Yang HH, Radomski MW, van Breemen C. 2008. Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in Marfan syndrome through the inhibition of matrix metalloproteinase-2 and -9. Circ. Res. 102:e73–85
    [Google Scholar]
  18. 18.
    Clarke MC, Littlewood TD, Figg N, Maguire JJ, Davenport AP et al. 2008. Chronic apoptosis of vascular smooth muscle cells accelerates atherosclerosis and promotes calcification and medial degeneration. Circ. Res. 102:1529–38
    [Google Scholar]
  19. 19.
    Cook JR, Clayton NP, Carta L, Galatioto J, Chiu E et al. 2015. Dimorphic effects of transforming growth factor-β signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome. Arterioscler. Thromb. Vasc. Biol. 35:911–17
    [Google Scholar]
  20. 20.
    Dasouki M, Markova D, Garola R, Sasaki T, Charbonneau NL et al. 2007. Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa. Am. J. Med. Genet. A 143A:2635–41
    [Google Scholar]
  21. 21.
    D'Hondt S, Van Damme T, Malfait F 2018. Vascular phenotypes in nonvascular subtypes of the Ehlers-Danlos syndrome: a systematic review. Genet. Med. 20:562–73
    [Google Scholar]
  22. 22.
    Dietz H. 2022. FBN1-related Marfan syndrome. GeneReviews MP Adam, HH Ardinger, RA Pagon, SE Wallace, LJH Bean, et al Seattle: Univ. Wash https://www.ncbi.nlm.nih.gov/books/NBK1335
    [Google Scholar]
  23. 23.
    Dikalov SI, Nazarewicz RR. 2013. Angiotensin II-induced production of mitochondrial reactive oxygen species: potential mechanisms and relevance for cardiovascular disease. Antioxid. Redox. Signal. 19:1085–94
    [Google Scholar]
  24. 24.
    Dinesh NEH, Reinhardt DP. 2019. Inflammation in thoracic aortic aneurysms. Herz 44:138–46
    [Google Scholar]
  25. 25.
    Dingemans KP, Teeling P, Lagendijk JH, Becker AE. 2000. Extracellular matrix of the human aortic media: an ultrastructural histochemical and immunohistochemical study of the adult aortic media. Anat. Rec. 258:1–14
    [Google Scholar]
  26. 26.
    Doyle AJ, Doyle JJ, Bessling SL, Maragh S, Lindsay ME et al. 2012. Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat. Genet. 44:1249–54
    [Google Scholar]
  27. 27.
    Duque Lasio ML, Kozel BA 2018. Elastin-driven genetic diseases. Matrix Biol. 71–72:144–60
    [Google Scholar]
  28. 28.
    Durdu S, Deniz GC, Balci D, Zaim C, Dogan A et al. 2012. Apoptotic vascular smooth muscle cell depletion via BCL2 family of proteins in human ascending aortic aneurysm and dissection. Cardiovasc. Ther. 30:308–16
    [Google Scholar]
  29. 29.
    Elbitar S, Renard M, Arnaud P, Hanna N, Jacob MP et al. 2021. Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm. Genet. Med. 23:111–22
    [Google Scholar]
  30. 30.
    Emrich F, Penov K, Arakawa M, Dhablania N, Burdon G et al. 2019. Anatomically specific reactive oxygen species production participates in Marfan syndrome aneurysm formation. J. Cell. Mol. Med. 23:7000–9
    [Google Scholar]
  31. 31.
    Fiorillo C, Becatti M, Attanasio M, Lucarini L, Nassi N et al. 2010. Evidence for oxidative stress in plasma of patients with Marfan syndrome. Int. J. Cardiol. 145:544–46
    [Google Scholar]
  32. 32.
    Franken R, Groenink M, de Waard V, Feenstra HM, Scholte AJ et al. 2016. Genotype impacts survival in Marfan syndrome. Eur. Heart J. 37:3285–90
    [Google Scholar]
  33. 33.
    Franken R, Teixido-Tura G, Brion M, Forteza A, Rodriguez-Palomares J et al. 2017. Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome. Heart 103:1795–99
    [Google Scholar]
  34. 34.
    Fukui D, Miyagawa S, Soeda J, Tanaka K, Urayama H, Kawasaki S. 2003. Overexpression of transforming growth factor β1 in smooth muscle cells of human abdominal aortic aneurysm. Eur. J. Vasc. Endovasc. Surg. 25:540–45
    [Google Scholar]
  35. 35.
    Galatioto J, Caescu CI, Hansen J, Cook JR, Miramontes I et al. 2018. Cell type–specific contributions of the angiotensin II type 1a receptor to aorta homeostasis and aneurysmal disease—brief report. Arterioscler. Thromb. Vasc. Biol. 38:588–91
    [Google Scholar]
  36. 36.
    Gao L, Chen L, Fan L, Gao D, Liang Z et al. 2016. The effect of losartan on progressive aortic dilatation in patients with Marfan's syndrome: a meta-analysis of prospective randomized clinical trials. Int. J. Cardiol. 217:190–94
    [Google Scholar]
  37. 37.
    Gasiulė S, Stankevičius V, Patamsytė V, Ražanskas R, Žukovas G et al. 2019. Tissue-specific miRNAs regulate the development of thoracic aortic aneurysm: the emerging role of KLF4 network. J. Clin. Med. 8:1609
    [Google Scholar]
  38. 38.
    Gorski DH, Walsh K. 2003. Control of vascular cell differentiation by homeobox transcription factors. Trends Cardiovasc. Med. 13:213–20
    [Google Scholar]
  39. 39.
    Goumans MJ, Liu Z, ten Dijke P. 2009. TGF-β signaling in vascular biology and dysfunction. Cell Res 19:116–27
    [Google Scholar]
  40. 40.
    Guemann AS, Andrieux J, Petit F, Halimi E, Bouquillon S et al. 2015. ELN gene triplication responsible for familial supravalvular aortic aneurysm. Cardiol. Young 25:712–17
    [Google Scholar]
  41. 41.
    Guilluy C, Burridge K. 2015. Nuclear mechanotransduction: forcing the nucleus to respond. Nucleus 6:19–22
    [Google Scholar]
  42. 42.
    Guo DC, Gong L, Regalado ES, Santos-Cortez RL, Zhao R et al. 2015. MAT2A mutations predispose individuals to thoracic aortic aneurysms. Am. J. Hum. Genet. 96:170–77
    [Google Scholar]
  43. 43.
    Guo DC, Grove ML, Prakash SK, Eriksson P, Hostetler EM et al. 2016. Genetic variants in LRP1 and ULK4 are associated with acute aortic dissections. Am. J. Hum. Genet. 99:762–69
    [Google Scholar]
  44. 44.
    Guo DC, Papke CL, Tran-Fadulu V, Regalado ES, Avidan N et al. 2009. Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am. J. Hum. Genet. 84:617–27
    [Google Scholar]
  45. 45.
    Guo DC, Regalado ES, Casteel DE, Santos-Cortez RL, Gong L et al. 2013. Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am. J. Hum. Genet. 93:398–404
    [Google Scholar]
  46. 46.
    Guo DC, Regalado ES, Gong L, Duan X, Santos-Cortez RL et al. 2016. LOX mutations predispose to thoracic aortic aneurysms and dissections. Circ. Res. 118:928–34
    [Google Scholar]
  47. 47.
    Guo DC, Regalado ES, Pinard A, Chen J, Lee K et al. 2018. LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections. Am. J. Hum. Genet. 102:706–12
    [Google Scholar]
  48. 48.
    Guo X, Fang ZM, Wei X, Huo B, Yi X et al. 2019. HDAC6 is associated with the formation of aortic dissection in human. Mol. Med. 25:10
    [Google Scholar]
  49. 49.
    Habashi JP, Doyle JJ, Holm TM, Aziz H, Schoenhoff F et al. 2011. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science 332:361–65
    [Google Scholar]
  50. 50.
    Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL et al. 2006. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312:117–21
    [Google Scholar]
  51. 51.
    Hadj-Rabia S, Callewaert BL, Bourrat E, Kempers M, Plomp AS et al. 2013. Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity. Orphanet J. Rare Dis. 8:36
    [Google Scholar]
  52. 52.
    Hansen J, Galatioto J, Caescu CI, Arnaud P, Calizo RC et al. 2019. Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms. JCI Insight 4:e127652
    [Google Scholar]
  53. 53.
    He D, Mao A, Zheng C-B, Kan H, Zhang K et al. 2020. Aortic heterogeneity across segments and under high fat/salt/glucose conditions at the single-cell level. Natl. Sci. Rev. 7:881–96
    [Google Scholar]
  54. 54.
    He R, Guo DC, Estrera AL, Safi HJ, Huynh TT et al. 2006. Characterization of the inflammatory and apoptotic cells in the aortas of patients with ascending thoracic aortic aneurysms and dissections. J. Thorac. Cardiovasc. Surg. 131:671–78
    [Google Scholar]
  55. 55.
    He R, Guo DC, Sun W, Papke CL, Duraisamy S et al. 2008. 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. 136:922–29.e1
    [Google Scholar]
  56. 56.
    Hibender S, Franken R, van Roomen C, Ter Braake A, van der Made I et al. 2016. Resveratrol inhibits aortic root dilatation in the Fbn1C1039G/+ Marfan mouse model. Arterioscler. Thromb. Vasc. Biol. 36:1618–26
    [Google Scholar]
  57. 57.
    Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF et al. 2010. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Catheter. Cardiovasc. Interv. 76:E43–86
    [Google Scholar]
  58. 58.
    Hofmann Bowman MA, Eagle KA, Milewicz DM. 2019. Update on clinical trials of losartan with and without β-blockers to block aneurysm growth in patients with Marfan syndrome: a review. JAMA Cardiol 4:702–7
    [Google Scholar]
  59. 59.
    Howard DP, Banerjee A, Fairhead JF, Perkins J, Silver LE et al. 2013. Population-based study of incidence and outcome of acute aortic dissection and premorbid risk factor control: 10-year results from the Oxford Vascular Study. Circulation 127:2031–37
    [Google Scholar]
  60. 60.
    Hsu CC, Chien WC, Wang JC, Chung CH, Liao WI et al. 2018. Association between atrial fibrillation and aortic aneurysms: a population-based cohort study. J. Vasc. Res. 55:299–307
    [Google Scholar]
  61. 61.
    Huang J, Davis EC, Chapman SL, Budatha M, Marmorstein LY et al. 2010. Fibulin-4 deficiency results in ascending aortic aneurysms: a potential link between abnormal smooth muscle cell phenotype and aneurysm progression. Circ. Res. 106:583–92
    [Google Scholar]
  62. 62.
    Humphrey JD, Schwartz MA, Tellides G, Milewicz DM. 2015. Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections. Circ. Res. 116:1448–61
    [Google Scholar]
  63. 63.
    Jimenez-Altayo F, Meirelles T, Crosas-Molist E, Sorolla MA, Del Blanco DG et al. 2018. Redox stress in Marfan syndrome: dissecting the role of the NADPH oxidase NOX4 in aortic aneurysm. Free Radic. . Biol. Med. 118:44–58
    [Google Scholar]
  64. 64.
    Jones JA, Spinale FG, Ikonomidis JS. 2009. Transforming growth factor-β signaling in thoracic aortic aneurysm development: a paradox in pathogenesis. J. Vasc. Res. 46:119–37
    [Google Scholar]
  65. 65.
    Ju X, Ijaz T, Sun H, Lejeune W, Vargas G et al. 2014. IL-6 regulates extracellular matrix remodeling associated with aortic dilation in a fibrillin-1 hypomorphic mgR/mgR mouse model of severe Marfan syndrome. J. Am. Heart Assoc. 3:e000476
    [Google Scholar]
  66. 66.
    Kan H, Zhang K, Mao A, Geng L, Gao M et al. 2021. Single-cell transcriptome analysis reveals cellular heterogeneity in the ascending aortas of normal and high-fat diet-fed mice. Exp. Mol. Med. 53:1379–89
    [Google Scholar]
  67. 67.
    Karimi A, Milewicz DM. 2016. 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. 32:26–34
    [Google Scholar]
  68. 68.
    Kimura N, Futamura K, Arakawa M, Okada N, Emrich F et al. 2017. Gene expression profiling of acute type A aortic dissection combined with in vitro assessment. Eur. J. Cardiothorac. Surg. 52:810–17
    [Google Scholar]
  69. 69.
    Kjellqvist S, Maleki S, Olsson T, Chwastyniak M, Branca RM et al. 2013. A combined proteomic and transcriptomic approach shows diverging molecular mechanisms in thoracic aortic aneurysm development in patients with tricuspid- and bicuspid aortic valve. Mol. Cell. Proteom. 12:407–25
    [Google Scholar]
  70. 70.
    Korneva A, Zilberberg L, Rifkin DB, Humphrey JD, Bellini C. 2019. Absence of LTBP-3 attenuates the aneurysmal phenotype but not spinal effects on the aorta in Marfan syndrome. Biomech. Model. Mechanobiol. 18:261–73
    [Google Scholar]
  71. 71.
    Koullias GJ, Ravichandran P, Korkolis DP, Rimm DL, Elefteriades JA. 2004. Increased tissue microarray matrix metalloproteinase expression favors proteolysis in thoracic aortic aneurysms and dissections. Ann. Thorac. Surg. 78:2106–10
    [Google Scholar]
  72. 72.
    Kuang SQ, Medina-Martinez O, Guo DC, Gong L, Regalado ES et al. 2016. FOXE3 mutations predispose to thoracic aortic aneurysms and dissections. J. Clin. Investig. 126:948–61
    [Google Scholar]
  73. 73.
    Kubiczkova L, Sedlarikova L, Hajek R, Sevcikova S. 2012. TGF-β – an excellent servant but a bad master. J. Transl. Med. 10:183
    [Google Scholar]
  74. 74.
    Landis BJ, Schubert JA, Lai D, Jegga AG, Shikany AR et al. 2017. Exome sequencing identifies candidate genetic modifiers of syndromic and familial thoracic aortic aneurysm severity. J. Cardiovasc. Transl. Res. 10:423–32
    [Google Scholar]
  75. 75.
    LeMaire SA, McDonald ML, Guo DC, Russell L, Miller CC III et al. 2011. Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. Nat. Genet. 43:996–1000
    [Google Scholar]
  76. 76.
    Li DY, Brooke B, Davis EC, Mecham RP, Sorensen LK et al. 1998. Elastin is an essential determinant of arterial morphogenesis. Nature 393:276–80
    [Google Scholar]
  77. 77.
    Li L, Yamani N, Al-Naimat S, Khurshid A, Usman MS. 2020. Role of losartan in prevention of aortic dilatation in Marfan syndrome: a systematic review and meta-analysis. Eur. J. Prev. Cardiol. 27:1447–50
    [Google Scholar]
  78. 78.
    Li X, Fang Q, Tian X, Wang X, Ao Q et al. 2017. Curcumin attenuates the development of thoracic aortic aneurysm by inhibiting VEGF expression and inflammation. Mol. Med. Rep. 16:4455–62
    [Google Scholar]
  79. 79.
    Li Y, Gao S, Han Y, Song L, Kong Y et al. 2021. Variants of focal adhesion scaffold genes cause thoracic aortic aneurysm. Circ. Res. 128:8–23
    [Google Scholar]
  80. 80.
    Li Y, Ren P, Dawson A, Vasquez HG, Ageedi W et al. 2020. Single-cell transcriptome analysis reveals dynamic cell populations and differential gene expression patterns in control and aneurysmal human aortic tissue. Circulation 142:1374–88
    [Google Scholar]
  81. 81.
    Liang L, Li X, Moutton S, Schrier Vergano SA, Cogne B et al. 2019. De novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes. Hum. Mol. Genet. 28:2937–51
    [Google Scholar]
  82. 82.
    Lino Cardenas CL, Kessinger CW, Cheng Y, MacDonald C, MacGillivray T et al. 2018. An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm. Nat. Commun. 9:1009
    [Google Scholar]
  83. 83.
    Liu C, Zhang C, Jia L, Chen B, Liu L et al. 2018. Interleukin-3 stimulates matrix metalloproteinase 12 production from macrophages promoting thoracic aortic aneurysm/dissection. Clin. Sci. 132:655–68
    [Google Scholar]
  84. 84.
    Liu P, Zhang J, Du D, Zhang D, Jin Z et al. 2021. Altered DNA methylation pattern reveals epigenetic regulation of Hox genes in thoracic aortic dissection and serves as a biomarker in disease diagnosis. Clin. Epigenet. 13:124
    [Google Scholar]
  85. 85.
    Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M et al. 2005. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet. 37:275–81
    [Google Scholar]
  86. 86.
    Loeys BL, Dietz HC 2018. Loeys-Dietz syndrome. GeneReviews MP Adam, HH Ardinger, RA Pagon, SE Wallace, LJH Bean, et al Seattle: Univ. Wash. https://www.ncbi.nlm.nih.gov/books/NBK1133
    [Google Scholar]
  87. 87.
    Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J et al. 2010. The revised Ghent nosology for the Marfan syndrome. J. Med. Genet. 47:476–85
    [Google Scholar]
  88. 88.
    Lu H, Rateri DL, Bruemmer D, Cassis LA, Daugherty A. 2012. Involvement of the renin-angiotensin system in abdominal and thoracic aortic aneurysms. Clin. Sci. 123:531–43
    [Google Scholar]
  89. 89.
    Luo W, Wang Y, Zhang L, Ren P, Zhang C et al. 2020. Critical role of cytosolic DNA and its sensing adaptor STING in aortic degeneration, dissection, and rupture. Circulation 141:42–66
    [Google Scholar]
  90. 90.
    Luyckx I, Bolar N, Diness BR, Hove HB, Verstraeten A, Loeys BL. 2019. Aortic aneurysm: an underestimated serious finding in the EP300 mutation phenotypical spectrum. Eur. J. Med. Genet. 62:96
    [Google Scholar]
  91. 91.
    Luyckx I, MacCarrick G, Kempers M, Meester J, Geryl C et al. 2019. Confirmation of the role of pathogenic SMAD6 variants in bicuspid aortic valve-related aortopathy. Eur. J. Hum. Genet. 27:1044–53
    [Google Scholar]
  92. 92.
    MacFarlane EG, Parker SJ, Shin JY, Kang BE, Ziegler SG et al. 2019. Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome. J. Clin. Investig. 129:659–75
    [Google Scholar]
  93. 93.
    Majesky MW. 2007. Developmental basis of vascular smooth muscle diversity. Arterioscler. Thromb. Vasc. Biol. 27:1248–58
    [Google Scholar]
  94. 94.
    Maleszewski JJ, Miller DV, Lu J, Dietz HC, Halushka MK. 2009. Histopathologic findings in ascending aortas from individuals with Loeys-Dietz syndrome (LDS). Am. J. Surg. Pathol. 33:194–201
    [Google Scholar]
  95. 95.
    Malfait F, Francomano C, Byers P, Belmont J, Berglund B et al. 2017. The 2017 international classification of the Ehlers-Danlos syndromes. Am. J. Med. Genet. C 175:8–26
    [Google Scholar]
  96. 96.
    Malhotra R, Mauer AC, Lino Cardenas CL, Guo X, Yao J et al. 2019. HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype. Nat. Genet. 51:1580–87
    [Google Scholar]
  97. 97.
    McClure RS, Brogly SB, Lajkosz K, Payne D, Hall SF, Johnson AP. 2018. Epidemiology and management of thoracic aortic dissections and thoracic aortic aneurysms in Ontario, Canada: a population-based study. J. Thorac. Cardiovasc. Surg. 155:2254–64.e4
    [Google Scholar]
  98. 98.
    Meester JA, Vandeweyer G, Pintelon I, Lammens M, Van Hoorick L et al. 2017. Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections. Genet. Med. 19:386–95
    [Google Scholar]
  99. 99.
    Micha D, Guo DC, Hilhorst-Hofstee Y, van Kooten F, Atmaja D et al. 2015. SMAD2 mutations are associated with arterial aneurysms and dissections. Hum. Mutat. 36:1145–49
    [Google Scholar]
  100. 100.
    Michel JB, Jondeau G, Milewicz DM. 2018. From genetics to response to injury: vascular smooth muscle cells in aneurysms and dissections of the ascending aorta. Cardiovasc. Res. 114:578–89
    [Google Scholar]
  101. 101.
    Morlino S, Alesi V, Cali F, Lepri FR, Secinaro A et al. 2019. LTBP2-related “Marfan-like” phenotype in two Roma/Gypsy subjects with the LTBP2 homozygous p.R299X variant. Am. J. Med. Genet. A 179:104–12
    [Google Scholar]
  102. 102.
    Moustakas A, Heldin CH. 2005. Non-Smad TGF-β signals. J. Cell Sci. 118:3573–84
    [Google Scholar]
  103. 103.
    Mullen M, Jin XY, Child A, Stuart AG, Dodd M et al. 2019. Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial. Lancet 394:2263–70
    [Google Scholar]
  104. 104.
    Nagasawa A, Yoshimura K, Suzuki R, Mikamo A, Yamashita O et al. 2013. Important role of the angiotensin II pathway in producing matrix metalloproteinase-9 in human thoracic aortic aneurysms. J. Surg. Res. 183:472–77
    [Google Scholar]
  105. 105.
    Nataatmadja M, West J, Prabowo S, West M. 2013. Angiotensin II receptor antagonism reduces transforming growth factor beta and Smad signaling in thoracic aortic aneurysm. Ochsner J 13:42–48
    [Google Scholar]
  106. 106.
    Nica AC, Dermitzakis ET. 2013. Expression quantitative trait loci: present and future. Philos. Trans. R. Soc. B 368:20120362
    [Google Scholar]
  107. 107.
    Nkomo VT, Enriquez-Sarano M, Ammash NM, Melton LJ III, Bailey KR et al. 2003. Bicuspid aortic valve associated with aortic dilatation: a community-based study. Arterioscler. Thromb. Vasc. Biol. 23:351–56
    [Google Scholar]
  108. 108.
    O'Connell MK, Murthy S, Phan S, Xu C, Buchanan J et al. 2008. The three-dimensional micro- and nanostructure of the aortic medial lamellar unit measured using 3D confocal and electron microscopy imaging. Matrix Biol 27:171–81
    [Google Scholar]
  109. 109.
    Oller J, Gabandé-Rodríguez E, Ruiz-Rodríguez MJ, Desdín-Micó G, Aranda JF et al. 2021. Extracellular tuning of mitochondrial respiration leads to aortic aneurysm. Circulation 143:2091–109
    [Google Scholar]
  110. 110.
    Oller J, Méndez-Barbero N, Ruiz EJ, Villahoz S, Renard M et al. 2017. Nitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndrome. Nat. Med. 23:200–12
    [Google Scholar]
  111. 111.
    Owens GK, Kumar MS, Wamhoff BR. 2004. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol. Rev. 84:767–801
    [Google Scholar]
  112. 112.
    Pan S, Wu D, Teschendorff AE, Hong T, Wang L et al. 2014. JAK2-centered interactome hotspot identified by an integrative network algorithm in acute Stanford type A aortic dissection. PLOS ONE 9:e89406
    [Google Scholar]
  113. 113.
    Pannu H, Tran-Fadulu V, Papke CL, Scherer S, Liu Y et al. 2007. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II. Hum. Mol. Genet. 16:2453–62
    [Google Scholar]
  114. 114.
    Park JE, Kim E, Lee DW, Park TK, Kim MS et al. 2021. Identification of de novo EP300 and PLAU variants in a patient with Rubinstein–Taybi syndrome-related arterial vasculopathy and skeletal anomaly. Sci. Rep. 11:15931
    [Google Scholar]
  115. 115.
    Pedroza AJ, Tashima Y, Shad R, Cheng P, Wirka R et al. 2020. Single-cell transcriptomic profiling of vascular smooth muscle cell phenotype modulation in Marfan syndrome aortic aneurysm. Arterioscler. Thromb. Vasc. Biol. 40:2195–211
    [Google Scholar]
  116. 116.
    Pepin MG, Schwarze U, Rice KM, Liu M, Leistritz D, Byers PH. 2014. Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV). Genet. Med. 16:881–88
    [Google Scholar]
  117. 117.
    Perrone RD, Malek AM, Watnick T. 2015. Vascular complications in autosomal dominant polycystic kidney disease. Nat. Rev. Nephrol. 11:589–98
    [Google Scholar]
  118. 118.
    Petsophonsakul P, Furmanik M, Forsythe R, Dweck M, Schurink GW et al. 2019. Role of vascular smooth muscle cell phenotypic switching and calcification in aortic aneurysm formation. Arterioscler. Thromb. Vasc. Biol. 39:1351–68
    [Google Scholar]
  119. 119.
    Pfaltzgraff ER, Shelton EL, Galindo CL, Nelms BL, Hooper CW et al. 2014. Embryonic domains of the aorta derived from diverse origins exhibit distinct properties that converge into a common phenotype in the adult. J. Mol. Cell. Cardiol. 69:88–96
    [Google Scholar]
  120. 120.
    Pirruccello JP, Chaffin MD, Chou EL, Fleming SJ, Lin H et al. 2021. Deep learning enables genetic analysis of the human thoracic aorta. Nature 54:30–51
    [Google Scholar]
  121. 121.
    Portelli SS, Hambly BD, Jeremy RW, Robertson EN 2021. Oxidative stress in genetically triggered thoracic aortic aneurysm: role in pathogenesis and therapeutic opportunities. Redox Rep 26:45–52
    [Google Scholar]
  122. 122.
    Ramnath NW, Hawinkels LJ, van Heijningen PM, te Riet L, Paauwe M et al. 2015. Fibulin-4 deficiency increases TGF-β signalling in aortic smooth muscle cells due to elevated TGF-β2 levels. Sci. Rep. 5:16872
    [Google Scholar]
  123. 123.
    Rateri DL, Davis FM, Balakrishnan A, Howatt DA, Moorleghen JJ et al. 2014. Angiotensin II induces region-specific medial disruption during evolution of ascending aortic aneurysms. Am. J. Pathol. 184:2586–95
    [Google Scholar]
  124. 124.
    Renard M, Francis C, Ghosh R, Scott AF, Witmer PD et al. 2018. Clinical validity of genes for heritable thoracic aortic aneurysm and dissection. J. Am. Coll. Cardiol. 72:605–15
    [Google Scholar]
  125. 125.
    Rifkin DB, Rifkin WJ, Zilberberg L. 2018. LTBPs in biology and medicine: LTBP diseases. Matrix Biol. 71–72:90–99
    [Google Scholar]
  126. 126.
    Rodrigues Bento J, Feben C, Kempers M, van Rij M, Woiski M et al. 2021. Two novel presentations of KCNMA1-related pathology—expanding the clinical phenotype of a rare channelopathy. Mol. Genet. Genom. Med. 9:e1797
    [Google Scholar]
  127. 127.
    Rodrigues Bento J, Krebsová A, Van Gucht I, Valdivia Callejon I, Van Berendoncks A et al. 2022. Isolated aneurysmal disease as an underestimated finding in individuals with JAG1 pathogenic variants. Authorea. https://doi.org/10.22541/au.164383426.69108413/v1
    [Crossref]
  128. 128.
    Roychowdhury T, Lu H, Hornsby WE, Crone B, Wang GT et al. 2021. Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm. Am. J. Hum. Genet. 108:1578–89
    [Google Scholar]
  129. 129.
    Rysz J, Gluba-Brzozka A, Rokicki R, Franczyk B. 2021. Oxidative stress-related susceptibility to aneurysm in Marfan's syndrome. Biomedicines 9:1171
    [Google Scholar]
  130. 130.
    Scola LG, Giarratana RM, Marinello V, Cancila V, Pisano C et al. 2021. Polymorphisms of pro-inflammatory IL-6 and IL-1β cytokines in ascending aortic aneurysms as genetic modifiers and predictive and prognostic biomarkers. Biomolecules 11:943
    [Google Scholar]
  131. 131.
    Shimizu K, Mitchell RN, Libby P. 2006. Inflammation and cellular immune responses in abdominal aortic aneurysms. Arterioscler. Thromb. Vasc. Biol. 26:987–94
    [Google Scholar]
  132. 132.
    Sulkava M, Raitoharju E, Mennander A, Levula M, Seppala I et al. 2017. Differentially expressed genes and canonical pathways in the ascending thoracic aortic aneurysm – the Tampere Vascular Study. Sci. Rep. 7:12127
    [Google Scholar]
  133. 133.
    Takeda N, Hara H, Fujiwara T, Kanaya T, Maemura S, Komuro I. 2018. TGF-β signaling-related genes and thoracic aortic aneurysms and dissections. Int. J. Mol. Sci. 19:2125
    [Google Scholar]
  134. 134.
    Tan KL, Haelterman NA, Kwartler CS, Regalado ES, Lee PT et al. 2018. Ari-1 regulates myonuclear organization together with parkin and is associated with aortic aneurysms. Dev. Cell 45:226–44.e8
    [Google Scholar]
  135. 135.
    Tang PC, Yakimov AO, Teesdale MA, Coady MA, Dardik A et al. 2005. Transmural inflammation by interferon-gamma-producing T cells correlates with outward vascular remodeling and intimal expansion of ascending thoracic aortic aneurysms. FASEB J 19:1528–30
    [Google Scholar]
  136. 136.
    Toomer K, Sauls K, Fulmer D, Guo L, Moore K et al. 2019. Filamin-A as a balance between Erk/Smad activities during cardiac valve development. Anat. Rec. 302:117–24
    [Google Scholar]
  137. 137.
    van der Pluijm I, Burger J, van Heijningen PM, IJpma A, van Vliet N et al. 2018. Decreased mitochondrial respiration in aneurysmal aortas of Fibulin-4 mutant mice is linked to PGC1A regulation. Cardiovasc. Res. 114:1776–93
    [Google Scholar]
  138. 138.
    Van Gucht I, Meester JAN, Rodrigues Bento J, Bastiaansen M, Bastianen J et al. 2021. A human importin-β-related disorder: syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8. Am. J. Hum. Genet. 108:1115–25
    [Google Scholar]
  139. 139.
    Vega-Lopez GA, Cerrizuela S, Tribulo C, Aybar MJ. 2018. Neurocristopathies: new insights 150 years after the neural crest discovery. Dev. Biol. 444:Suppl. 1S110–43
    [Google Scholar]
  140. 140.
    Verstraeten A, Luyckx I, Loeys B. 2017. Aetiology and management of hereditary aortopathy. Nat. Rev. Cardiol. 14:197–208
    [Google Scholar]
  141. 141.
    Wan YY, Flavell RA. 2008. TGF-β and regulatory T cell in immunity and autoimmunity. J. Clin. Immunol. 28:647–59
    [Google Scholar]
  142. 142.
    Wang L, Guo DC, Cao J, Gong L, Kamm KE et al. 2010. Mutations in myosin light chain kinase cause familial aortic dissections. Am. J. Hum. Genet. 87:701–7
    [Google Scholar]
  143. 143.
    Wang M, Zhang J, Spinetti G, Jiang LQ, Monticone R et al. 2005. Angiotensin II activates matrix metalloproteinase type II and mimics age-associated carotid arterial remodeling in young rats. Am. J. Pathol. 167:1429–42
    [Google Scholar]
  144. 144.
    Wang X, Charng WL, Chen CA, Rosenfeld JA, Al Shamsi A et al. 2017. Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations. Nat. Genet. 49:613–17
    [Google Scholar]
  145. 145.
    Weis-Muller BT, Modlich O, Drobinskaya I, Unay D, Huber R et al. 2006. Gene expression in acute Stanford type A dissection: a comparative microarray study. J. Transl. Med. 4:29
    [Google Scholar]
  146. 146.
    Yang HH, van Breemen C, Chung AW. 2010. Vasomotor dysfunction in the thoracic aorta of Marfan syndrome is associated with accumulation of oxidative stress. Vascul. Pharmacol. 52:37–45
    [Google Scholar]
  147. 147.
    Ye P, Chen W, Wu J, Huang X, Li J et al. 2013. GM-CSF contributes to aortic aneurysms resulting from SMAD3 deficiency. J. Clin. Investig. 123:2317–31
    [Google Scholar]
  148. 148.
    Yu E, Foote K, Bennett M. 2018. Mitochondrial function in thoracic aortic aneurysms. Cardiovasc. Res. 114:1696–98
    [Google Scholar]
  149. 149.
    Zhang L, Liao MF, Tian L, Zou SL, Lu QS et al. 2011. Overexpression of interleukin-1β and interferon-gamma in type I thoracic aortic dissections and ascending thoracic aortic aneurysms: possible correlation with matrix metalloproteinase-9 expression and apoptosis of aortic media cells. Eur. J. Cardiothorac. Surg. 40:17–22
    [Google Scholar]
  150. 150.
    Zhou X, Cheng J, Chen Z, Li H, Chen S et al. 2020. Role of c-Abl in Ang II-induced aortic dissection formation: potential regulatory efficacy on phenotypic transformation and apoptosis of VSMCs. Life Sci 256:117882
    [Google Scholar]
  151. 151.
    Zhou Z, Liu Y, Zhu X, Tang X, Wang Y et al. 2020. Exaggerated autophagy in Stanford type A aortic dissection: a transcriptome pilot analysis of human ascending aortic tissues. Genes 11:1187
    [Google Scholar]
  152. 152.
    Ziegler A, Duclaux-Loras R, Revenu C, Charbit-Henrion F, Begue B et al. 2021. Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation. Am. J. Hum. Genet. 108:1126–37
    [Google Scholar]
/content/journals/10.1146/annurev-genom-111521-104455
Loading
/content/journals/10.1146/annurev-genom-111521-104455
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error