Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-β Signaling

EBioMedicine

Volumn 12, Issue , 2016, Pages 280-294

  van der Pluijm, I ^a   van Vliet, N ^a   von der Thusen, J H ^a   Robertus, J L ^a   Ridwan, Y ^a   van Heijningen, P M ^a   van Thiel, B S ^a   Vermeij, M ^a   Hoeks, S E ^a   Buijs Offerman, R M G B ^a   Verhagen, H J M ^a   Kanaar, R ^a   Bertoli Avella, A M ^a,b   Essers, J ^a  

^a ERASMUS MEDICAL CENTER   (Netherlands)

^b CENTOGENE AG   (Germany)

Author keywords

Aneurysm; Echocardiography; Mouse model; TGF signaling pathway; Vascular biology

Indexed keywords

ELASTIN; MATRIX METALLOPROTEINASE; MITOGEN ACTIVATED PROTEIN KINASE; SMAD3 PROTEIN; TISSUE INHIBITOR OF METALLOPROTEINASE 1; TRANSFORMING GROWTH FACTOR BETA; SMAD2 PROTEIN;

ANIMAL CELL; ANIMAL TISSUE; AORTA ANEURYSM; ARTICLE; B SCAN; CELL PROLIFERATION ASSAY; COMPUTER ASSISTED TOMOGRAPHY; CONTROLLED STUDY; DEATH; ECHOCARDIOGRAPHY; FEMALE; IMMUNOHISTOCHEMISTRY; INFLAMMATION; MALE; MOLECULAR IMAGING; MOUSE; NONHUMAN; OSTEOARTHRITIS; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; REAL TIME POLYMERASE CHAIN REACTION; RNA ISOLATION; SIGNAL TRANSDUCTION; TRANSCRIPTION REGULATION; VASCULAR SMOOTH MUSCLE CELL; WESTERN BLOTTING; ANEURYSM; ANIMAL; AORTIC ANEURYSM; BIOLOGICAL MODEL; CELL PROLIFERATION; CONNECTIVE TISSUE; DEFICIENCY; DISEASE MODEL; GENETICS; KNOCKOUT MOUSE; METABOLISM; MICRO-COMPUTED TOMOGRAPHY; MORTALITY; PATHOLOGY; TRANSCRIPTION INITIATION; VASCULAR SMOOTH MUSCLE;

ANEURYSM; ANIMALS; AORTIC ANEURYSM; CELL PROLIFERATION; CONNECTIVE TISSUE; DISEASE MODELS, ANIMAL; ECHOCARDIOGRAPHY; ELASTIN; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; FEMALE; IMMUNOHISTOCHEMISTRY; INFLAMMATION; MALE; MATRIX METALLOPROTEINASES; MICE; MICE, KNOCKOUT; MODELS, BIOLOGICAL; MOLECULAR IMAGING; MORTALITY; MUSCLE, SMOOTH, VASCULAR; SIGNAL TRANSDUCTION; SMAD2 PROTEIN; SMAD3 PROTEIN; TRANSCRIPTIONAL ACTIVATION; TRANSFORMING GROWTH FACTOR BETA; X-RAY MICROTOMOGRAPHY;

EID: 84992578655     PISSN: None     EISSN: 23523964     Source Type: Journal    
DOI: 10.1016/j.ebiom.2016.09.006     Document Type: Article

References (52)

1. Akhurst, R.J., The paradoxical TGF-beta vasculopathies. Nat. Genet. 44 (2012), 838–839.
2. Albornoz, G., Coady, M.A., Roberts, M., Davies, R.R., Tranquilli, M., Rizzo, J.A., Elefteriades, J.A., Familial thoracic aortic aneurysms and dissections—incidence, modes of inheritance, and phenotypic patterns. Ann. Thorac. Surg. 82 (2006), 1400–1405.
3. Aubart, M., Gobert, D., Aubart-Cohen, F., Detaint, D., Hanna, N., D'Indya, H., Lequintrec, J.S., Renard, P., Vigneron, A.M., Dieude, P., Laissy, J.P., Koch, P., Muti, C., Roume, J., Cusin, V., Grandchamp, B., Gouya, L., Leguern, E., Papo, T., Boileau, C., Jondeau, G., Early-onset osteoarthritis, Charcot-Marie-Tooth like neuropathy, autoimmune features, multiple arterial aneurysms and dissections: an unrecognized and life threatening condition. PLoS One, 9, 2014, e96387.
4. Bertoli-Avella, A.M., Gillis, E., Morisaki, H., Verhagen, J.M., de Graaf, B.M., Van de Beek, G., Gallo, E., Kruithof, B.P., Venselaar, H., Myers, L.A., Laga, S., Doyle, A.J., Oswald, G., Van Cappellen, G.W., Yamanaka, I., Van der Helm, R.M., Beverloo, B., de Klein, A., Pardo, L., Lammens, M., Evers, C., Devriendt, K., Dumoulein, M., Timmermans, J., Bruggenwirth, H.T., Verheijen, F., Rodrigus, I., Baynam, G., Kempers, M., Saenen, J., Van Craenenbroeck, E.M., Minatoya, K., Matsukawa, R., Tsukube, T., Kubo, N., Hofstra, R., Goumans, M.J., Bekkers, J.A., Roos-Hesselink, J.W., Van de Laar, I.M., Dietz, H.C., Van Laer, L., Morisaki, T., Wessels, M.W., Loeys, B.L., Mutations in a TGF-beta ligand, TGFB3, cause syndromic aortic aneurysms and dissections. J. Am. Coll. Cardiol. 65 (2015), 1324–1336.
5. Boileau, C., Guo, D.C., Hanna, N., Regalado, E.S., Detaint, D., Gong, L., Varret, M., Prakash, S.K., Li, A.H., D'Indy, H., Braverman, A.C., Grandchamp, B., Kwartler, C.S., Gouya, L., Santos-Cortez, R.L., Abifadel, M., Leal, S.M., Muti, C., Shendure, J., Gross, M.S., Rieder, M.J., Vahanian, A., Nickerson, D.A., Michel, J.B., National Heart, L., Blood Institute Go Exome Sequencing, P., Jondeau, G., Milewicz, D.M., TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat. Genet. 44 (2012), 916–921.
6. Chung, A.W., Au Yeung, K., Sandor, G.G., Judge, D.P., Dietz, H.C., Van Breemen, C., Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and − 9 in the thoracic aortic aneurysm in Marfan syndrome. Circ. Res. 101 (2007), 512–522.
7. Cohn, R.D., Van Erp, C., Habashi, J.P., Soleimani, A.A., Klein, E.C., Lisi, M.T., Gamradt, M., Ap Rhys, C.M., Holm, T.M., Loeys, B.L., Ramirez, F., Judge, D.P., Ward, C.W., Dietz, H.C., Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat. Med. 13 (2007), 204–210.
8. Dennler, S., Itoh, S., Vivien, D., Ten Dijke, P., Huet, S., Gauthier, J.M., Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J. 17 (1998), 3091–3100.
9. Fitzgerald, K.K., Bhat, A.M., Conard, K., Hyland, J., Pizarro, C., Novel SMAD3 mutation in a patient with hypoplastic left heart syndrome with significant aortic aneurysm. Case Rep. Genet., 2014, 2014, 591516.
10. Gillis, E., Van Laer, L., Loeys, B.L., Genetics of thoracic aortic aneurysm: at the crossroad of transforming growth factor-beta signaling and vascular smooth muscle cell contractility. Circ. Res. 113 (2013), 327–340.
11. Grubb, K.J., Kron, I.L., Sex and gender in thoracic aortic aneurysms and dissection. Semin. Thorac. Cardiovasc. Surg. 23 (2011), 124–125.
12. Guo, D.C., Pannu, H., Tran-Fadulu, V., Papke, C.L., Yu, R.K., Avidan, N., Bourgeois, S., Estrera, A.L., Safi, H.J., Sparks, E., Amor, D., Ades, L., McConnell, V., Willoughby, C.E., Abuelo, D., Willing, M., Lewis, R.A., Kim, D.H., Scherer, S., Tung, P.P., Ahn, C., Buja, L.M., Raman, C.S., Shete, S.S., Milewicz, D.M., Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat. Genet. 39 (2007), 1488–1493.
13. Habashi, J.P., Judge, D.P., Holm, T.M., Cohn, R.D., Loeys, B.L., Cooper, T.K., Myers, L., Klein, E.C., Liu, G., Calvi, C., Podowski, M., Neptune, E.R., Halushka, M.K., Bedja, D., Gabrielson, K., Rifkin, D.B., Carta, L., Ramirez, F., Huso, D.L., Dietz, H.C., Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312 (2006), 117–121.
14. Hanada, K., Vermeij, M., Garinis, G.A., de Waard, M.C., Kunen, M.G., Myers, L., Maas, A., Duncker, D.J., Meijers, C., Dietz, H.C., Kanaar, R., Essers, J., Perturbations of vascular homeostasis and aortic valve abnormalities in fibulin-4 deficient mice. Circ. Res. 100 (2007), 738–746.
15. Hawinkels, L.J., Paauwe, M., Verspaget, H.W., Wiercinska, E., Van der Zon, J.M., Van der Ploeg, K., Koelink, P.J., Lindeman, J.H., Mesker, W., Ten Dijke, P., Sier, C.F., Interaction with colon cancer cells hyperactivates TGF-beta signaling in cancer-associated fibroblasts. Oncogene 33 (2014), 97–107.
16. Hilhorst-Hofstee, Y., Scholte, A.J., Rijlaarsdam, M.E., Van Haeringen, A., Kroft, L.J., Reijnierse, M., Ruivenkamp, C.A., Versteegh, M.I., Pals, G., Breuning, M.H., An unanticipated copy number variant of chromosome 15 disrupting SMAD3 reveals a three-generation family at serious risk for aortic dissection. Clin. Genet. 83 (2013), 337–344.
17. Huang, J., Davis, E.C., Chapman, S.L., Budatha, M., Marmorstein, L.Y., Word, R.A., Yanagisawa, H., Fibulin-4 deficiency results in ascending aortic aneurysms: a potential link between abnormal smooth muscle cell phenotype and aneurysm progression. Circ. Res. 106 (2010), 583–592.
18. Kaijzel, E.L., Van Heijningen, P.M., Wielopolski, P.A., Vermeij, M., Koning, G.A., Van Cappellen, W.A., Que, I., Chan, A., Dijkstra, J., Ramnath, N.W., Hawinkels, L.J., Bernsen, M.R., Lowik, C.W., Essers, J., Multimodality imaging reveals a gradual increase in matrix metalloproteinase activity at aneurysmal lesions in live fibulin-4 mice. Circ. Cardiovasc. Imaging 3 (2010), 567–577.
19. Lemaitre, V., Soloway, P.D., D'Armiento, J., Increased medial degradation with pseudo-aneurysm formation in apolipoprotein E-knockout mice deficient in tissue inhibitor of metalloproteinases-1. Circulation 107 (2003), 333–338.
20. Li, T.F., Darowish, M., Zuscik, M.J., Chen, D., Schwarz, E.M., Rosier, R.N., Drissi, H., O'Keefe, R.J., Smad3-deficient chondrocytes have enhanced BMP signaling and accelerated differentiation. J. Bone Miner. Res. 21 (2006), 4–16.
21. Li, C.G., Liang, Q.Q., Zhou, Q., Menga, E., Cui, X.J., Shu, B., Zhou, C.J., Shi, Q., Wang, Y.J., A continuous observation of the degenerative process in the intervertebral disc of Smad3 gene knock-out mice. Spine (Phila Pa 1976) 34 (2009), 1363–1369.
22. Lindsay, M.E., Dietz, H.C., Lessons on the pathogenesis of aneurysm from heritable conditions. Nature 473 (2011), 308–316.
23. Lindsay, M.E., Schepers, D., Bolar, N.A., Doyle, J.J., Gallo, E., Fert-Bober, J., Kempers, M.J., Fishman, E.K., Chen, Y., Myers, L., Bjeda, D., Oswald, G., Elias, A.F., Levy, H.P., Anderlid, B.M., Yang, M.H., Bongers, E.M., Timmermans, J., Braverman, A.C., Canham, N., Mortier, G.R., Brunner, H.G., Byers, P.H., Van Eyk, J., Van Laer, L., Dietz, H.C., Loeys, B.L., Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat. Genet. 44 (2012), 922–927.
24. Loeys, B.L., Chen, J., Neptune, E.R., Judge, D.P., Podowski, M., Holm, T., Meyers, J., Leitch, C.C., Katsanis, N., Sharifi, N., Xu, F.L., Myers, L.A., Spevak, P.J., Cameron, D.E., de Backer, J., Hellemans, J., Chen, Y., Davis, E.C., Webb, C.L., Kress, W., Coucke, P., Rifkin, D.B., de Paepe, A.M., Dietz, H.C., A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet., 37, 2005, 275–281.
25. Longo, G.M., Xiong, W., Greiner, T.C., Zhao, Y., Fiotti, N., Baxter, B.T., Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J. Clin. Invest. 110 (2002), 625–632.
26. Martens, T., Van Herzeele, I., de Ryck, F., renard, M., de Paepe, A., Francois, K., Vermassen, F., de Backer, J., Multiple aneurysms in a patient with aneurysms-osteoarthritis syndrome. Ann. Thorac. Surg. 95 (2013), 332–335.
27. Massague, J., TGFbeta signalling in context. Nat. Rev. Mol. Cell Biol. 13 (2012), 616–630.
28. Massague, J., Seoane, J., Wotton, D., Smad transcription factors. Genes Dev. 19 (2005), 2783–2810.
29. McAllister, K.A., Grogg, K.M., Johnson, D.W., Gallione, C.J., Baldwin, M.A., Jackson, C.E., Helmbold, E.A., Markel, D.S., McKinnon, W.C., Murrell, J., et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat. Genet. 8 (1994), 345–351.
30. McLaughlin, P.J., Chen, Q., Horiguchi, M., Starcher, B.C., Stanton, J.B., Broekelmann, T.J., Marmorstein, A.D., McKay, B., Mecham, R., Nakamura, T., Marmorstein, L.Y., Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. Mol. Cell. Biol. 26 (2006), 1700–1709.
31. Mizuguchi, T., Collod-Beroud, G., Akiyama, T., Abifadel, M., Harada, N., Morisaki, T., Allard, D., Varret, M., Claustres, M., Morisaki, H., Ihara, M., Kinoshita, A., Yoshiura, K., Junien, C., Kajii, T., Jondeau, G., Ohta, T., Kishino, T., Furukawa, Y., Nakamura, Y., Niikawa, N., Boileau, C., Matsumoto, N., Heterozygous TGFBR2 mutations in Marfan syndrome. Nat. Genet. 36 (2004), 855–860.
32. Moltzer, E., Te Riet, L., Swagemakers, S.M., Van Heijningen, P.M., Vermeij, M., Van Veghel, R., Bouhuizen, A.M., Van Esch, J.H., Lankhorst, S., Ramnath, N.W., de Waard, M.C., Duncker, D.J., Van der Spek, P.J., Rouwet, E.V., Danser, A.H., Essers, J., Impaired vascular contractility and aortic wall degeneration in fibulin-4 deficient mice: effect of angiotensin II type 1 (AT1) receptor blockade. PLoS One, 6, 2011, e23411.
33. Moustakas, A., Heldin, C.H., From mono- to oligo-Smads: the heart of the matter in TGF-beta signal transduction. Genes Dev. 16 (2002), 1867–1871.
34. Nahrendorf, M., Keliher, E., Marinelli, B., Leuschner, F., Robbins, C.S., Gerszten, R.E., Pittet, M.J., Swirski, F.K., Weissleder, R., Detection of macrophages in aortic aneurysms by nanoparticle positron emission tomography-computed tomography. Arterioscler. Thromb. Vasc. Biol. 31 (2011), 750–757.
35. Neptune, E.R., Frischmeyer, P.A., Arking, D.E., Myers, L., Bunton, T.E., Gayraud, B., Ramirez, F., Sakai, L.Y., Dietz, H.C., Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat. Genet. 33 (2003), 407–411.
36. Ng, C.M., Cheng, A., Myers, L.A., Martinez-Murillo, F., Jie, C., Bedja, D., Gabrielson, K.L., Hausladen, J.M., Mecham, R.P., Judge, D.P., Dietz, H.C., TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J. Clin. Invest. 114 (2004), 1586–1592.
37. Ramnath, N.W., Hawinkels, L.J., Van Heijningen, P.M., Riet, L.T., Paauwe, M., Vermeij, M., Danser, A.H., Kanaar, R., Ten Dijke, P., Essers, J., Fibulin-4 deficiency increases TGF-beta signalling in aortic smooth muscle cells due to elevated TGF-beta2 levels. Sci. Rep., 5, 2015, 16872.
38. Regalado, E.S., Guo, D.C., Villamizar, C., Avidan, N., Gilchrist, D., McGillivray, B., Clarke, L., Bernier, F., Santos-Cortez, R.L., Leal, S.M., Bertoli-Avella, A.M., Shendure, J., Rieder, M.J., Nickerson, D.A., Project, N. G. E. S., Milewicz, D.M., Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circ. Res., 109, 2011, 680–686.
39. Renard, M., Holm, T., Veith, R., Callewaert, B.L., Ades, L.C., Baspinar, O., Pickart, A., Dasouki, M., Hoyer, J., Rauch, A., Trapane, P., Earing, M.G., Coucke, P.J., Sakai, L.Y., Dietz, H.C., de Paepe, A.M., Loeys, B.L., Altered TGFbeta signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency. Eur. J. Hum. Genet. 18 (2010), 895–901.
40. Renard, M., Callewaert, B., Baetens, M., Campens, L., MacDermot, K., Fryns, J.P., Bonduelle, M., Dietz, H.C., Gaspar, I.M., Cavaco, D., Stattin, E.L., Schrander-Stumpel, C., Coucke, P., Loeys, B., de Paepe, A., de Backer, J., Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFbeta signaling in FTAAD. Int. J. Cardiol. 165 (2013), 314–321.
41. Rienhoff, H.Y.J., Yeo, C.Y., Morissette, R., Khrebtukova, I., Melnick, J., Luo, S., Leng, N., Kim, Y.J., Schroth, G., Westwick, J., Vogel, H., McDonnell, N., Hall, J.G., Whitman, M., A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome. Am. J. Med. Genet. A 161A (2013), 2040–2046.
42. Segura, A.M., Luna, R.E., Horiba, K., Stetler-Stevenson, W.G., Mcallister, H.A. Jr., Willerson, J.T., Ferrans, V.J., Immunohistochemistry of matrix metalloproteinases and their inhibitors in thoracic aortic aneurysms and aortic valves of patients with Marfan's syndrome. Circulation 98 (1998), II331–II337 discussion II337–8.
43. Te Riet, L., Van Deel, E.D., Van Thiel, B.S., Moltzer, E., Van Vliet, N., Ridwan, Y., Van Veghel, R., Van Heijningen, P.M., Robertus, J.L., Garrelds, I.M., Vermeij, M., Van der Pluijm, I., Danser, A.H., Essers, J., AT1-receptor blockade, but not renin inhibition, reduces aneurysm growth and cardiac failure in fibulin-4 mice. J. Hypertens. 34 (2016), 654–665.
44. Van de Laar, I.M., Oldenburg, R.A., Pals, G., Roos-Hesselink, J.W., de Graaf, B.M., Verhagen, J.M., Hoedemaekers, Y.M., Willemsen, R., Severijnen, L.A., Venselaar, H., Vriend, G., Pattynama, P.M., Collee, M., Majoor-Krakauer, D., Poldermans, D., Frohn-Mulder, I.M., Micha, D., Timmermans, J., Hilhorst-Hofstee, Y., Bierma-Zeinstra, S.M., Willems, P.J., Kros, J.M., Oei, E.H., Oostra, B.A., Wessels, M.W., Bertoli-Avella, A.M., Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat. Genet. 43 (2011), 121–126.
45. Van de Laar, I.M., Van der Linde, D., Oei, E.H., Bos, P.K., Bessems, J.H., Bierma-Zeinstra, S.M., Van Meer, B.L., Pals, G., Oldenburg, R.A., Bekkers, J.A., Moelker, A., de Graaf, B.M., Matyas, G., Frohn-Mulder, I.M., Timmermans, J., Hilhorst-Hofstee, Y., Cobben, J.M., Bruggenwirth, H.T., Van Laer, L., Loeys, B., de Backer, J., Coucke, P.J., Dietz, H.C., Willems, P.J., Oostra, B.A., de Paepe, A., Roos-Hesselink, J.W., Bertoli-Avella, A.M., Wessels, M.W., Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J. Med. Genet. 49 (2012), 47–57.
46. Van der Linde, D., Van de Laar, I.M., Bertoli-Avella, A.M., Oldenburg, R.A., Bekkers, J.A., Mattace-Raso, F.U., Van den Meiracker, A.H., Moelker, A., Van Kooten, F., Frohn-Mulder, I.M., Timmermans, J., Moltzer, E., Cobben, J.M., Van Laer, L., Loeys, B., de Backer, J., Coucke, P.J., de Paepe, A., Hilhorst-Hofstee, Y., Wessels, M.W., Roos-Hesselink, J.W., Aggressive cardiovascular phenotype of aneurysms-osteoarthritis syndrome caused by pathogenic SMAD3 variants. J. Am. Coll. Cardiol. 60 (2012), 397–403.
47. Van der Linde, D., Van de Laar, I., Moelker, A., Wessels, M.W., Bertoli-Avella, A.M., Roos-Hesselink, J.W., Patients with aneurysms and osteoarthritis: Marfan syndrome ruled out, so what is it?] Patienten met aneurysmata en osteoartritis: geen syndroom van Marfan, maar wat dan?. Ned. Tijdschr. Geneeskd., 157, 2013, A5588.
48. Wischmeijer, A., Van Laer, L., Tortora, G., Bolar, N.A., Van Camp, G., Fransen, E., Peeters, N., Di Bartolomeo, R., Pacini, D., Gargiulo, G., Turci, S., Bonvicini, M., Mariucci, E., Lovato, L., Brusori, S., Ritelli, M., Colombi, M., Garavelli, L., Seri, M., Loeys, B.L., Thoracic aortic aneurysm in infancy in aneurysms-osteoarthritis syndrome due to a novel SMAD3 mutation: further delineation of the phenotype. Am. J. Med. Genet. A 161A (2013), 1028–1035.
49. Yang, X., Cao, X., Smad interactors in bone morphogenetic protein signaling. Methods Mol. Biol. 177 (2001), 163–178.
50. Ye, P., Chen, W., Wu, J., Huang, X., Li, J., Wang, S., Liu, Z., Wang, G., Yang, X., Zhang, P., Lv, Q., Xia, J., GM-CSF contributes to aortic aneurysms resulting from SMAD3 deficiency. J. Clin. Invest. 123 (2013), 2317–2331.
51. Zhang, Y., Feng, X., We, R., Derynck, R., Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature 383 (1996), 168–172.
52. Zhu, L., Vranckx, R., Khau Van Kien, P., Lalande, A., Boisset, N., Mathieu, F., Wegman, M., Glancy, L., Gasc, J.M., Brunotte, F., Bruneval, P., Wolf, J.E., Michel, J.B., Jeunemaitre, X., Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat. Genet., 38, 2006, 343–349.