Table of Contents

    Topic review

    Thoracic Aortic Aneurysms

    Subjects: Others
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    Definition

    Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin–myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β).

    1. Introduction

    Aneurysms are permanent, localized dilatations of an artery greater than 50% of the normal diameter. They progressively dilate while remaining mostly asymptomatic until a life-threatening rupture and/or dissection occurs [1]. Prophylactic surgical repair remains the only proven method to prevent risk of death caused by mechanical failure of the vessel [2]. Aneurysms can develop both in the thoracic and abdominal aorta [3]. Aneurysms that affect the abdominal aorta are more common, tend to occur in older individuals, and have no known monogenic cause, although multiple candidate risk loci have been reported [4][5][6]. While less common, thoracic aortic aneurysms (TAA) can develop in the absence of cardiovascular risk factors, affect younger individuals, and have a higher degree of heritability [6][7]. Although a hereditary predisposition to TAA confers an increased risk of aortopathy to all segments of the vessel, pathogenic mechanisms can differ depending on the specific aortic location [8][9]. For example, dissections of the thoracic descending aorta can occur even when dilation is limited or absent and as a complication of proximal aortic repair [10][11][12]. Hereditary forms of TAA are subdivided into syndromic and non-syndromic depending on the presence or absence of manifestations in other organ systems [13]. Syndromic forms of TAA occur in patients affected by connective tissue disorders such as Marfan syndrome (MFS) and Loeys–Dietz syndrome (LDS) [13], all of which have manifestations in organ systems other than the aorta. In contrast, TAAs in hereditary non-syndromic thoracic aortic disease are not usually associated with overt defects in other connective tissues [13]. Several causative genes for both syndromic and non-syndromic TAA have been identified, leading to a better understanding of the mechanisms by which this condition develops [14].

    2. Adaptive and Maladaptive Responses in TAA: Implications for Therapy

    We have a limited understanding of the compensatory mechanisms activated in response to germline TAA-associated mutations. Feedback responses attempting to offset the negative consequences of a given genetic variant are active throughout prenatal and postnatal development and might significantly modify the structural, cellular, and molecular properties of the adult aorta. Mechanisms that are adaptive early, such as the activation of secondary pathways that compensate for the initial deficiency, might become maladaptive later on due to divergent effects on adult versus embryonic tissues, over-activation, or secondary activation of deleterious pathways. This might be especially true for mutations that impair signaling involved in morphogenesis, such as TGF-β and Notch signaling, given that the mitigation of defective signaling in these pathways is a condition necessary for the development of vascular structures and survival [15][16][17]. Additionally, while it is tempting to assume that all the phenotypic changes observed in TAA at the structural, cellular, and molecular level are contributing factors to disease, some may represent ongoing beneficial compensatory responses.

    2.1. Adaptive and Maladaptive Roles of “Aortic Stiffness”

    Loss of elastin and the increased deposition and crosslinking of collagen during aneurysm development translate into biomechanical changes that include reduced distensibility and increased stiffness of the aorta [18]. Changes in stiffness modulate VSMCs phenotypes through integrins and focal adhesions; although stiffness is generally associated with the retention of a “contractile” phenotype, excess stiffness can also increase sensitivity to growth factors, such as PDGF, which promotes a “synthetic” phenotype, and enhanced ECM stiffness has been shown to promote a switch from a “contractile” to a “synthetic” phenotype through the downregulation of DNA methyltransferase 1 [19][20][21][22].

    Perhaps unintuitively, increased stiffness (resistance to deformation) can associate with decreased vessel strength (ability to withstand stress without breaking), with one study measuring an approximately 30% decrease in vessel strength accompanied by a 72% increase in stiffness in aneurysmal versus nonaneurysmal ascending aorta [23][24]. Correlations between increased stiffness and aortic dilatation have been reported in numerous studies of both patients and mouse models of TAA [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39].

    Although measures of distensibility and circumferential strain lose predictive power once aortic diameter is included in the analysis, a recent study of one hundred and seventeen MFS patients showed that measurements of longitudinal strain in the proximal aorta was a predictor of adverse aortic events (such as elective aortic root surgery or dissection), thus providing support to the notion that aortic stiffness could be considered for the stratification of patients based on risk [25][40][41].

    These observations may suggest that increased collagen deposition and crosslinking is uniformly deleterious in TAA. However, other studies have shown that collagen deposition, especially in the adventitial layer, can be protective and part of beneficial “scar repair” mechanisms preventing transmural ruptures [18][24][42][43]. Consistent with these latter observations, genetic or pharmacological inactivation of lysyl oxidases, enzymes necessary for collagen and elastin cross-linking, cause or exacerbate aneurysm in patients and animal models [44][45][46][47][48][49][50][51][52]. The detrimental effects of fluoroquinolones on TAA pathogenesis have also been attributed to excess ECM degradation and reduced levels of collagen [53][54][55][56].

    Taken together, these data suggest that the deposition of properly crosslinked collagen confers strength to the vessel, thus protecting it from mechanical failure. However, its effect might be highly dependent on the type and quality of collagen and the effect of ECM stiffness on VSMC phenotypes [18][57][58][59][60]. In vitro experiments in which levels of stiffness can be experimentally modulated show that both overly soft and overly stiff substrates fail to support functional focal adhesions and actin–myosin dynamics, and that nanoscale level patterning of substrata that mimics physiological conditions can modulate the effect of stiffness; VSMCs grown on nanopatterned soft substrata had a higher expression of VSMC markers associated with a quiescent, contractile phenotype (smoothelin, calponin-1), and lower expression of inflammatory markers (monocyte chemoattractant protein-1) relative to nanopatterned “stiff” substrata, suggesting that matrix architecture and mechanics have combinatorial effects on VSMC mechanosensing and differentiation pathways [57][58][60].

    2.2. Adaptive and Maladaptive Roles of TGF-β Signaling

    Work performed in animal models clearly shows that TGF-β signaling is essential for aortic development and morphogenesis [61][62]. Additionally, the ablation of TGF-β signaling in VSMCs by the genetic inactivation of Tgfbr2 postnatally results in aortopathy and dissections as well as an exacerbation of pathology in mice with a pre-existing genetic predisposition to aortic aneurysm, suggesting that postnatal aortic VSMCs require a basal level of TGF-β signaling for homeostasis [63][64][65]. Moreover, as discussed, heterozygous, inactivating mutations in positive effectors of this pathway cause hereditary forms of TAA [66][67][68][69][70][71][72][73][74][75][76]. In consequence of these observations, the increased levels of TGF-β ligand and nuclear pSmad2/3 observed in aneurysmal tissue obtained from patients and models carrying these mutations has been proposed to be part of a “repair” response [5][77].

    Beneficial roles of TGF-β in TAA may include the suppression of AT1R signaling, induction of protective factors such as nexin-1 and proteases inhibitors, and promotion of contractile proteins expression [63][78][79][80][81][82]. In addition, TGF-β-dependent induction of collagen, lysyl oxidases, and other pro-fibrotic factors might contribute to thickening of the adventitial layer, which, as discussed, can be protective [18][48][83][84][85][86][87]. On the other hand, maladaptive effects of excess TGF-β signaling include an induction of glycosaminoglycans and proteoglycan accumulation within the arterial wall, upregulation of proteolytic enzymes that exacerbate ECM destruction, and stimulation of ROS production thorough several mechanisms, including by upregulation of NADPH oxidases (Nox) [88][89][90][91][92][93][94][95][96][97][98][99].

    Accordingly, in contrast to the complete inactivation of TGF-β signaling in VSMCs, which unvaryingly enhances pathogenesis, the effect of partial TGF-β antagonism with neutralizing antibodies or by the inactivation of Smad proteins in selected cellular subsets is varied. Systemic TGF-β neutralization had no effect on angiotensin II-induced TAA [100], and it either had a beneficial or dimorphic effect in mouse models of MFS, with perinatal and postnatal antagonism being detrimental and beneficial, respectively [101][102][103]. In a recent study in a MFS mouse model, the beneficial effect of TGF-β neutralizing antibodies was correlated with a reduced expression of Nox4, restoration of normal levels of dihydrofolate reductase, and reduced levels of ROS production [103]. Additional studies in mouse models of hereditary TAA have shown that while germline Smad4 haploinsufficiency is deleterious in MFS, Smad2 deletion in CNC-derived VSMCs is beneficial in a mouse model of LDS [104][105]. Taken together, these data indicate that TGF-β signaling can serve both protective and pathogenic roles in TAA depending both on cell type and stage of disease [106][107].

    2.3. Adaptive and Maladaptive Roles of Angiotensin II Signaling

    In contrast with direct TGF-β antagonism, treatment with antagonists of AT1R signaling, such as the angiotensin receptor blocker (ARB) losartan, invariably prevents the development of aneurysm in animal models; this beneficial effect associates with reduced levels of TGF-β ligand, pSmad2/3, and the expression of TGF-β target genes [108][109][101][110][111][112][113]. In addition, the deletion of Agtr1a (gene encoding AT1R in mice) prevents aortic root dilation in two different MFS mouse models [114][115]. The beneficial effects of AT1R antagonism in mouse models of TAA have been attributed to its anti-hypertensive effects and to the inhibition of fibrotic, hypertrophic, and mitogenic responses activated by TGF-β and mitogen-activated protein kinase (MAPK) signaling [159,258][105][116]. Additionally, losartan treatment could reduce the AT1R-dependent secretion of glycosaminoglycans, whose accumulation has deleterious effects on the aortic wall [88][117]. Based on this evidence, several clinical trials have been initiated to test the efficacy of AT1R antagonism in the treatment of aneurysm in MFS patients. Although the degree of efficacy varied, none of the studies could replicate the remarkable beneficial effects routinely achieved in pre-clinical models; in one trial, the rate of adverse events was higher in the losartan-treatment group than in those receiving a hemodynamically equivalent dose of anti-hypertensive medication [118][119][120][121][122][123][124][125][126][127].

    These results raised the possibility that AT1R signaling might have protective effects in TAA, both directly and through the enhancement of any protective effects of TGF-β signaling [128][129]. For example, the inhibition of AT1R-dependent collagen deposition and maturation, directly or through TGF-β-dependent pathways, could recapitulate, in part the detrimental effect of lysyl oxidase inhibition with β-amino-propionitrile (BAPN), which causes dissection or rupture in a number of animal models [47][50][51][52][84][85][87][130][131]. Additionally, AT1R-dependent signaling could be beneficial through stimulation of VSMC contraction [128][132]. Although the potential for beneficial effects of AT1R signaling need to be considered, other reasons may account for different outcomes in clinical trials relative to mouse models [108][133].

    In mouse trials, losartan has been tested primarily in prevention rather than treatment of aneurysm, given that in most studies, the drug is initiated early, before overt disease is apparent; this is not the case for clinical trials, given that many patients have established aneurysms when treatment is started [134]. Additionally, in mouse trials, this drug is administered continuously throughout the day in drinking water or by an osmotic pump, at doses of approximately 50-100 mg/Kg/day; this is relevant because losartan has a short half-life of approximately 2 h [134] and the human equivalent dose [135] for the one used in mice would be 4–8 mg/Kg/day, which is much higher than the 0.4 to 1.5 mg/Kg/day used in clinical trials. In view of these considerations, it is notable that a recent double-blind, placebo-controlled, randomized clinical trial testing the effect of higher doses of irbesartan, an ARB with a longer half-life than losartan, significantly reduced aortic root dilatation in MFS patients [136].

    The relative low frequency of adverse aortic events (dissection, rupture, death) makes it difficult to perform clinical trials with sufficient power to assess the effect of treatment on these clinically relevant outcomes, and most trials rely on the measurement of aortic size or growth to assess efficacy. Despite the statistical limitations, the most recent metanalysis of available data showed that AT1R antagonism slows the progression of aortic root dilation and is not associated with a statistically significant difference in adverse aortic events [32][137]. Additionally, a recently published long-term follow-up of the multicenter COMPARE trial, which originally reported a small but significant reduction in aortic root dilatation [138], showed that losartan treatment in MFS patients was associated with a decreased number of adverse aortic events in the treatment group [138]. Although more studies with sufficient power to confirm this study are both needed and planned, losartan is currently considered an acceptable treatment in combination with β-adrenergic receptor blockers, or when the latter are not tolerated [108][50].

    The entry is from 10.3390/genes12020183

    References

    1. Melvinsdottir, I.H.; Lund, S.H.; Agnarsson, B.A.; Sigvaldason, K.; Gudbjartsson, T.; Geirsson, A. The incidence and mortality of acute thoracic aortic dissection: Results from a whole nation study. Eur. J. Cardiothorac. Surg. 2016, 50, 1111–1117.
    2. Hiratzka, L.F.; Bakris, G.L.; Beckman, J.A.; Bersin, R.M.; Carr, V.F.; Casey, D.E., Jr.; Eagle, K.A.; Hermann, L.K.; Isselbacher, E.M.; Kazerooni, E.A.; et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: 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. Circulation 2010, 121, e266–e369.
    3. Quintana, R.A.; Taylor, W.R. Introduction to the Compendium on Aortic Aneurysms. Circ. Res. 2019, 124, 470–471.
    4. Wong, D.R.; Willett, W.C.; Rimm, E.B. Smoking, hypertension, alcohol consumption, and risk of abdominal aortic aneurysm in men. Am. J. Epidemiol. 2007, 165, 838–845.
    5. Pinard, A.; Jones, G.T.; Milewicz, D.M. Genetics of Thoracic and Abdominal Aortic Diseases. Circ. Res. 2019, 124, 588–606.
    6. Bossone, E.; Eagle, K.A. Epidemiology and management of aortic disease: Aortic aneurysms and acute aortic syndromes. Nat. Rev. Cardiol. 2020.
    7. Vapnik, J.S.; Kim, J.B.; Isselbacher, E.M.; Ghoshhajra, B.B.; Cheng, Y.; Sundt, T.M., 3rd; MacGillivray, T.E.; Cambria, R.P.; Lindsay, M.E. Characteristics and Outcomes of Ascending Versus Descending Thoracic Aortic Aneurysms. Am. J. Cardiol. 2016, 117, 1683–1690.
    8. Isselbacher, E.M. Thoracic and abdominal aortic aneurysms. Circulation 2005, 111, 816–828.
    9. Saeyeldin, A.A.; Velasquez, C.A.; Mahmood, S.U.B.; Brownstein, A.J.; Zafar, M.A.; Ziganshin, B.A.; Elefteriades, J.A. Thoracic aortic aneurysm: Unlocking the “silent killer” secrets. Gen. Thorac. Cardiovasc. Surg. 2019, 67, 1–11.
    10. LeMaire, S.A.; Russell, L. Epidemiology of thoracic aortic dissection. Nat. Rev. Cardiol. 2011, 8, 103–113.
    11. den Hartog, A.W.; Franken, R.; Zwinderman, A.H.; Timmermans, J.; Scholte, A.J.; van den Berg, M.P.; de Waard, V.; Pals, G.; Mulder, B.J.; Groenink, M. The risk for type B aortic dissection in Marfan syndrome. J. Am. Coll. Cardiol. 2015, 65, 246–254.
    12. LaBounty, T.M.; Eagle, K.A. Distal aorta: The next frontier in managing Marfan syndrome aortic disease. J. Am. Coll. Cardiol. 2015, 65, 255–256.
    13. Mulder, B.J.M.; van de Laar, I.M.B.H.; De Backer, J. Heritable Thoracic Aortic Diseases: Syndromal and Isolated (F)TAAD. In Clinical Cardiogenetics; Baars, H.F., Doevendans, P.A.F.M., Houweling, A.C., van Tintelen, J.P., Eds.; Springer International Publishing: Cham, Switzerland, 2020; pp. 309–343.
    14. Chou, E.L.; Lindsay, M.E. The genetics of aortopathies: Hereditary thoracic aortic aneurysms and dissections. Am. J. Med. Genet. C. Semin. Med. Genet. 2020, 184, 136–148.
    15. Malashicheva, A.; Kostina, A.; Kostareva, A.; Irtyuga, O.; Gordeev, M.; Uspensky, V. Notch signaling in the pathogenesis of thoracic aortic aneurysms: A bridge between embryonic and adult states. Biochim Biophys Acta Mol. Basis Dis 2020, 1866, 165631.
    16. Azhar, M.; Schultz Jel, J.; Grupp, I.; Dorn, G.W., 2nd; Meneton, P.; Molin, D.G.; Gittenberger-de Groot, A.C.; Doetschman, T. Transforming growth factor β in cardiovascular development and function. Cytokine Growth Factor Rev. 2003, 14, 391–407.
    17. Chakrabarti, M.; Al-Sammarraie, N.; Gebere, M.G.; Bhattacharya, A.; Chopra, S.; Johnson, J.; Pena, E.A.; Eberth, J.F.; Poelmann, R.E.; Gittenberger-de Groot, A.C.; et al. Transforming Growth Factor Beta3 is Required for Cardiovascular Development. J. Cardiovasc. Dev. Dis. 2020, 7, 19.
    18. Humphrey, J.D.; Tellides, G. Central artery stiffness and thoracic aortopathy. Am. J. Physiol. Heart Circ. Physiol. 2019, 316, H169–H182
    19. Yamashiro, Y.; Yanagisawa, H. The molecular mechanism of mechanotransduction in vascular homeostasis and disease. Clin. Sci. 2020, 134, 2399–2418.
    20. Kothapalli, D.; Liu, S.L.; Bae, Y.H.; Monslow, J.; Xu, T.; Hawthorne, E.A.; Byfield, F.J.; Castagnino, P.; Rao, S.; Rader, D.J.; et al. Cardiovascular protection by ApoE and ApoE-HDL linked to suppression of ECM gene expression and arterial stiffening. Cell Rep. 2012, 2, 1259–1271.
    21. Brown, X.Q.; Bartolak-Suki, E.; Williams, C.; Walker, M.L.; Weaver, V.M.; Wong, J.Y. Effect of substrate stiffness and PDGF on the behavior of vascular smooth muscle cells: Implications for atherosclerosis. J. Cell Physiol. 2010, 225, 115–122.
    22. Xie, S.A.; Zhang, T.; Wang, J.; Zhao, F.; Zhang, Y.P.; Yao, W.J.; Hur, S.S.; Yeh, Y.T.; Pang, W.; Zheng, L.S.; et al. Matrix stiffness determines the phenotype of vascular smooth muscle cell in vitro and in vivo: Role of DNA methyltransferase 1. Biomaterials 2018, 155, 203–216.
    23. Vorp, D.A.; Schiro, B.J.; Ehrlich, M.P.; Juvonen, T.S.; Ergin, M.A.; Griffith, B.P. Effect of aneurysm on the tensile strength and biomechanical behavior of the ascending thoracic aorta. Ann. Thorac. Surg. 2003, 75, 1210–1214.
    24. Duprey, A.; Trabelsi, O.; Vola, M.; Favre, J.P.; Avril, S. Biaxial rupture properties of ascending thoracic aortic aneurysms. Acta. Biomater. 2016, 42, 273–285.
    25. Nollen, G.J.; Groenink, M.; Tijssen, J.G.; Van Der Wall, E.E.; Mulder, B.J. Aortic stiffness and diameter predict progressive aortic dilatation in patients with Marfan syndrome. Eur. Heart J. 2004, 25, 1146–1152.
    26. Baumgartner, D.; Baumgartner, C.; Matyas, G.; Steinmann, B.; Loffler-Ragg, J.; Schermer, E.; Schweigmann, U.; Baldissera, I.; Frischhut, B.; Hess, J.; et al. Diagnostic power of aortic elastic properties in young patients with Marfan syndrome. J. Thorac. Cardiovasc. Surg. 2005, 129, 730–739.
    27. Pees, C.; Michel-Behnke, I. Morphology of the bicuspid aortic valve and elasticity of the adjacent aorta in children. Am. J. Cardiol. 2012, 110, 1354–1360.
    28. Oulego-Erroz, I.; Alonso-Quintela, P.; Mora-Matilla, M.; Gautreaux Minaya, S.; Lapena-Lopez de Armentia, S. Ascending aorta elasticity in children with isolated bicuspid aortic valve. Int. J. Cardiol. 2013, 168, 1143–1146.
    29. Teixido-Tura, G.; Redheuil, A.; Rodriguez-Palomares, J.; Gutierrez, L.; Sanchez, V.; Forteza, A.; Lima, J.A.; Garcia-Dorado, D.; Evangelista, A. Aortic biomechanics by magnetic resonance: Early markers of aortic disease in Marfan syndrome regardless of aortic dilatation? Int. J. Cardiol. 2014, 171, 56–61.
    30. Teixido-Tura, G.; Evangelista, A. Response to Letter by Mkrtchyan regarding article: “Aortic biomechanics by magnetic resonance: Early markers of aortic disease in Marfan syndrome regardless of aortic dilatation?”. Int. J. Cardiol. 2014, 176, 287.
    31. Mkrtchyan, N.; Fratz, S. Correspondence letter by Mkrtchyan and Fratz regarding article “aortic biomechanics by magnetic resonance: Early markers of aortic disease in Marfan syndrome regardless of aortic dilatation?”. Int. J. Cardiol. 2014, 174, 381.
    32. Weismann, C.G.; Lombardi, K.C.; Grell, B.S.; Northrup, V.; Sugeng, L. Aortic stiffness and left ventricular diastolic function in children with well-functioning bicuspid aortic valves. Eur. Heart J. Cardiovasc. Imaging 2016, 17, 225–230.
    33. Bellini, C.; Korneva, A.; Zilberberg, L.; Ramirez, F.; Rifkin, D.B.; Humphrey, J.D. Differential ascending and descending aortic mechanics parallel aneurysmal propensity in a mouse model of Marfan syndrome. J. Biomech. 2016, 49, 2383–2389.
    34. Lee, J.J.; Galatioto, J.; Rao, S.; Ramirez, F.; Costa, K.D. Losartan Attenuates Degradation of Aorta and Lung Tissue Micromechanics in a Mouse Model of Severe Marfan Syndrome. Ann. Biomed. Eng. 2016, 44, 2994–3006.
    35. Devos, D.G.; De Groote, K.; Babin, D.; Demulier, L.; Taeymans, Y.; Westenberg, J.J.; Van Bortel, L.; Segers, P.; Achten, E.; De Schepper, J.; et al. Proximal aortic stiffening in Turner patients may be present before dilation can be detected: A segmental functional MRI study. J. Cardiovasc. Magn. Reson. 2017, 19, 27.
    36. Bellini, C.; Bersi, M.R.; Caulk, A.W.; Ferruzzi, J.; Milewicz, D.M.; Ramirez, F.; Rifkin, D.B.; Tellides, G.; Yanagisawa, H.; Humphrey, J.D. Comparison of 10 murine models reveals a distinct biomechanical phenotype in thoracic aortic aneurysms. J. R Soc. Interface 2017, 14, 20161036‎.
    37. Selamet Tierney, E.S.; Levine, J.C.; Sleeper, L.A.; Roman, M.J.; Bradley, T.J.; Colan, S.D.; Chen, S.; Campbell, M.J.; Cohen, M.S.; De Backer, J.; et al. Influence of Aortic Stiffness on Aortic-Root Growth Rate and Outcome in Patients With the Marfan Syndrome. Am. J. Cardiol. 2018, 121, 1094–1101.
    38. Goudot, G.; Mirault, T.; Bruneval, P.; Soulat, G.; Pernot, M.; Messas, E. Aortic Wall Elastic Properties in Case of Bicuspid Aortic Valve. Front. Physiol. 2019, 10, 299.
    39. Chen, J.Z.; Sawada, H.; Moorleghen, J.J.; Weiland, M.; Daugherty, A.; Sheppard, M.B. Aortic Strain Correlates with Elastin Fragmentation in Fibrillin-1 Hypomorphic Mice. Circ. Rep. 2019, 1, 199–205.
    40. Prakash, A.; Adlakha, H.; Rabideau, N.; Hass, C.J.; Morris, S.A.; Geva, T.; Gauvreau, K.; Singh, M.N.; Lacro, R.V. Segmental Aortic Stiffness in Children and Young Adults With Connective Tissue Disorders: Relationships With Age, Aortic Size, Rate of Dilation, and Surgical Root Replacement. Circulation 2015, 132, 595–602.
    41. Guala, A.; Teixido-Tura, G.; Rodriguez-Palomares, J.; Ruiz-Munoz, A.; Dux-Santoy, L.; Villalva, N.; Granato, C.; Galian, L.; Gutierrez, L.; Gonzalez-Alujas, T.; et al. Proximal aorta longitudinal strain predicts aortic root dilation rate and aortic events in Marfan syndrome. Eur. Heart J. 2019, 40, 2047–2055.
    42. de Wit, A.; Vis, K.; Jeremy, R.W. Aortic stiffness in heritable aortopathies: Relationship to aneurysm growth rate. Heart Lung Circ. 2013, 22, 3–11.
    43. Bellini, C.; Ferruzzi, J.; Roccabianca, S.; Di Martino, E.S.; Humphrey, J.D. A microstructurally motivated model of arterial wall mechanics with mechanobiological implications. Ann. Biomed. Eng. 2014, 42, 488–502.
    44. Lee, V.S.; Halabi, C.M.; Hoffman, E.P.; Carmichael, N.; Leshchiner, I.; Lian, C.G.; Bierhals, A.J.; Vuzman, D.; Brigham Genomic, M.; Mecham, R.P.; et al. Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proc. Natl. Acad. Sci. USA 2016, 113, 8759–8764.
    45. Guo, D.C.; Regalado, E.S.; Gong, L.; Duan, X.; Santos-Cortez, R.L.; Arnaud, P.; Ren, Z.; Cai, B.; Hostetler, E.M.; Moran, R.; et al. LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections. Circ. Res. 2016, 118, 928–934.
    46. Maki, J.M.; Rasanen, J.; Tikkanen, H.; Sormunen, R.; Makikallio, K.; Kivirikko, K.I.; Soininen, R. Inactivation of the lysyl oxidase gene Lox leads to aortic aneurysms, cardiovascular dysfunction, and perinatal death in mice. Circulation 2002, 106, 2503–2509.
    47. Busnadiego, O.; Gorbenko Del Blanco, D.; Gonzalez-Santamaria, J.; Habashi, J.P.; Calderon, J.F.; Sandoval, P.; Bedja, D.; Guinea-Viniegra, J.; Lopez-Cabrera, M.; Rosell-Garcia, T.; et al. Elevated expression levels of lysyl oxidases protect against aortic aneurysm progression in Marfan syndrome. J. Mol. Cell Cardiol. 2015, 85, 48–57.
    48. Powell, J.T.; Lanne, T. Through thick and thin collagen fibrils, stress, and aortic rupture: Another piece in the jigsaw. Circulation 2007, 115, 2687–2688.
    49. de Figueiredo Borges, L.; Jaldin, R.G.; Dias, R.R.; Stolf, N.A.; Michel, J.B.; Gutierrez, P.S. Collagen is reduced and disrupted in human aneurysms and dissections of ascending aorta. Hum. Pathol. 2008, 39, 437–443.
    50. Barnett, B.D.; Bird, H.R.; Lalich, J.J.; Strong, F.M. Toxicity of β-amino-propionitrile for turkey poults. Proc. Soc. Exp. Biol. Med. 1957, 94, 67–70.
    51. Terpin, T.; Roach, M.R. A biophysical and histological analysis of factors that lead to aortic rupture in normal and lathyritic turkeys. Can. J. Physiol. Pharmacol. 1987, 65, 395–400.
    52. Li, J.S.; Li, H.Y.; Wang, L.; Zhang, L.; Jing, Z.P. Comparison of β-aminopropionitrile-induced aortic dissection model in rats by different administration and dosage. Vascular 2013, 21, 287–292.
    53. Lee, C.C.; Lee, M.T.; Chen, Y.S.; Lee, S.H.; Chen, Y.S.; Chen, S.C.; Chang, S.C. Risk of Aortic Dissection and Aortic Aneurysm in Patients Taking Oral Fluoroquinolone. JAMA Intern. Med. 2015, 175, 1839–1847.
    54. LeMaire, S.A.; Zhang, L.; Luo, W.; Ren, P.; Azares, A.R.; Wang, Y.; Zhang, C.; Coselli, J.S.; Shen, Y.H. Effect of Ciprofloxacin on Susceptibility to Aortic Dissection and Rupture in Mice. JAMA Surg. 2018, 153, e181804.
    55. Noman, A.T.; Qazi, A.H.; Alqasrawi, M.; Ayinde, H.; Tleyjeh, I.M.; Lindower, P.; Bin Abdulhak, A.A. Fluoroquinolones and the risk of aortopathy: A systematic review and meta-analysis. Int. J. Cardiol. 2019, 274, 299–302.
    56. Guzzardi, D.G.; Teng, G.; Kang, S.; Geeraert, P.J.; Pattar, S.S.; Svystonyuk, D.A.; Belke, D.D.; Fedak, P.W.M. Induction of human aortic myofibroblast-mediated extracellular matrix dysregulation: A potential mechanism of fluoroquinolone-associated aortopathy. J. Thorac. Cardiovasc. Surg. 2019, 157, 109–119.
    57. Peyton, S.R.; Putnam, A.J. Extracellular matrix rigidity governs smooth muscle cell motility in a biphasic fashion. J. Cell Physiol. 2005, 204, 198–209.
    58. Lindeman, J.H.; Ashcroft, B.A.; Beenakker, J.W.; van Es, M.; Koekkoek, N.B.; Prins, F.A.; Tielemans, J.F.; Abdul-Hussien, H.; Bank, R.A.; Oosterkamp, T.H. Distinct defects in collagen microarchitecture underlie vessel-wall failure in advanced abdominal aneurysms and aneurysms in Marfan syndrome. Proc. Natl. Acad. Sci. USA 2010, 107, 862–865.
    59. Sazonova, O.V.; Lee, K.L.; Isenberg, B.C.; Rich, C.B.; Nugent, M.A.; Wong, J.Y. Cell-cell interactions mediate the response of vascular smooth muscle cells to substrate stiffness. Biophys. J. 2011, 101, 622–630.
    60. Chaterji, S.; Kim, P.; Choe, S.H.; Tsui, J.H.; Lam, C.H.; Ho, D.S.; Baker, A.B.; Kim, D.H. Synergistic effects of matrix nanotopography and stiffness on vascular smooth muscle cell function. Tissue Eng. Part. A 2014, 20, 2115–2126.
    61. Choudhary, B.; Zhou, J.; Li, P.; Thomas, S.; Kaartinen, V.; Sucov, H.M. Absence of TGFbeta signaling in embryonic vascular smooth muscle leads to reduced lysyl oxidase expression, impaired elastogenesis, and aneurysm. Genesis 2009, 47, 115–121.
    62. Choudhary, B.; Ito, Y.; Makita, T.; Sasaki, T.; Chai, Y.; Sucov, H.M. Cardiovascular malformations with normal smooth muscle differentiation in neural crest-specific type II TGFbeta receptor (Tgfbr2) mutant mice. Dev. Biol. 2006, 289, 420–429.
    63. Li, W.; Li, Q.; Jiao, Y.; Qin, L.; Ali, R.; Zhou, J.; Ferruzzi, J.; Kim, R.W.; Geirsson, A.; Dietz, H.C.; et al. Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis. J. Clin. Investig. 2014, 124, 755–767.
    64. Hu, J.H.; Wei, H.; Jaffe, M.; Airhart, N.; Du, L.; Angelov, S.N.; Yan, J.; Allen, J.K.; Kang, I.; Wight, T.N.; et al. Postnatal Deletion of the Type II Transforming Growth Factor-β Receptor in Smooth Muscle Cells Causes Severe Aortopathy in Mice. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 2647–2656.
    65. Wei, H.; Hu, J.H.; Angelov, S.N.; Fox, K.; Yan, J.; Enstrom, R.; Smith, A.; Dichek, D.A. 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.
    66. Loeys, B.L.; Chen, J.; Neptune, E.R.; Judge, D.P.; Podowski, M.; Holm, T.; Meyers, J.; Leitch, C.C.; Katsanis, N.; Sharifi, N.; et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet. 2005, 37, 275–281.
    67. 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.; et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat. Genet. 2011, 43, 121–126.
    68. Micha, D.; Guo, D.C.; Hilhorst-Hofstee, Y.; van Kooten, F.; Atmaja, D.; Overwater, E.; Cayami, F.K.; Regalado, E.S.; van Uffelen, R.; Venselaar, H.; et al. SMAD2 Mutations Are Associated with Arterial Aneurysms and Dissections. Hum. Mutat. 2015, 36, 1145–1149.
    69. 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.; et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat. Genet. 2012, 44, 922–927.
    70. 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.; et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat. Genet. 2012, 44, 916–921.
    71. 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.; et al. Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. J. Am. Coll. Cardiol. 2015, 65, 1324–1336.
    72. Inamoto, S.; Kwartler, C.S.; Lafont, A.L.; Liang, Y.Y.; Fadulu, V.T.; Duraisamy, S.; Willing, M.; Estrera, A.; Safi, H.; Hannibal, M.C.; et al. TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections. Cardiovasc. Res. 2010, 88, 520–529.
    73. 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.; et al. Aggressive cardiovascular phenotype of aneurysms-osteoarthritis syndrome caused by pathogenic SMAD3 variants. J. Am. Coll. Cardiol. 2012, 60, 397–403.
    74. 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.; et al. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J. Med. Genet. 2012, 49, 47–57.
    75. Wischmeijer, A.; Van Laer, L.; Tortora, G.; Bolar, N.A.; Van Camp, G.; Fransen, E.; Peeters, N.; di Bartolomeo, R.; Pacini, D.; Gargiulo, G.; et al. 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 2013, 161A, 1028–1035.
    76. Schepers, D.; Tortora, G.; Morisaki, H.; MacCarrick, G.; Lindsay, M.; Liang, D.; Mehta, S.G.; Hague, J.; Verhagen, J.; van de Laar, I.; et al. A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. Hum. Mutat. 2018, 39, 621–634.
    77. Michel, J.B.; Jondeau, G.; Milewicz, D.M. From genetics to response to injury: Vascular smooth muscle cells in aneurysms and dissections of the ascending aorta. Cardiovasc. Res. 2018, 114, 578–589.
    78. Qiu, P.; Ritchie, R.P.; Fu, Z.; Cao, D.; Cumming, J.; Miano, J.M.; Wang, D.Z.; Li, H.J.; Li, L. Myocardin enhances Smad3-mediated transforming growth factor-beta1 signaling in a CArG box-independent manner: Smad-binding element is an important cis element for SM22alpha transcription in vivo. Circ. Res. 2005, 97, 983–991.
    79. Kwak, H.J.; Park, M.J.; Cho, H.; Park, C.M.; Moon, S.I.; Lee, H.C.; Park, I.C.; Kim, M.S.; Rhee, C.H.; Hong, S.I. Transforming growth factor-beta1 induces tissue inhibitor of metalloproteinase-1 expression via activation of extracellular signal-regulated kinase and Sp1 in human fibrosarcoma cells. Mol. Cancer Res. 2006, 4, 209–220.
    80. Zhang, X.H.; Zheng, B.; Gu, C.; Fu, J.R.; Wen, J.K. TGF-beta1 downregulates AT1 receptor expression via PKC-delta-mediated Sp1 dissociation from KLF4 and Smad-mediated PPAR-γ association with KLF4. Arterioscler. Thromb. Vasc. Biol. 2012, 32, 1015–1023.
    81. Gomez, D.; Kessler, K.; Borges, L.F.; Richard, B.; Touat, Z.; Ollivier, V.; Mansilla, S.; Bouton, M.C.; Alkoder, S.; Nataf, P.; et al. Smad2-dependent protease nexin-1 overexpression differentiates chronic aneurysms from acute dissections of human ascending aorta. Arterioscler. Thromb. Vasc. Biol. 2013, 33, 2222–2232.
    82. Ferruzzi, J.; Murtada, S.I.; Li, G.; Jiao, Y.; Uman, S.; Ting, M.Y.; Tellides, G.; Humphrey, J.D. Pharmacologically Improved Contractility Protects Against Aortic Dissection in Mice With Disrupted Transforming Growth Factor-β Signaling Despite Compromised Extracellular Matrix Properties. Arterioscler. Thromb. Vasc. Biol. 2016, 36, 919–927.
    83. Gacheru, S.N.; Thomas, K.M.; Murray, S.A.; Csiszar, K.; Smith-Mungo, L.I.; Kagan, H.M. Transcriptional and post-transcriptional control of lysyl oxidase expression in vascular smooth muscle cells: Effects of TGF-β 1 and serum deprivation. J. Cell Biochem. 1997, 65, 395–407.
    84. Ignotz, R.A.; Massague, J. Transforming growth factor-β stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J. Biol. Chem. 1986, 261, 4337–4345.
    85. Lindahl, G.E.; Chambers, R.C.; Papakrivopoulou, J.; Dawson, S.J.; Jacobsen, M.C.; Bishop, J.E.; Laurent, G.J. Activation of fibroblast procollagen α 1(I) transcription by mechanical strain is transforming growth factor-β-dependent and involves increased binding of CCAAT-binding factor (CBF/NF-Y) at the proximal promoter. J. Biol. Chem. 2002, 277, 6153–6161.
    86. Goel, S.A.; Guo, L.W.; Shi, X.D.; Kundi, R.; Sovinski, G.; Seedial, S.; Liu, B.; Kent, K.C. Preferential secretion of collagen type 3 versus type 1 from adventitial fibroblasts stimulated by TGF-β/Smad3-treated medial smooth muscle cells. Cell Signal. 2013, 25, 955–960.
    87. Hong, H.H.; Trackman, P.C. Cytokine regulation of gingival fibroblast lysyl oxidase, collagen, and elastin. J. Periodontol. 2002, 73, 145–152.
    88. Humphrey, J.D. Possible mechanical roles of glycosaminoglycans in thoracic aortic dissection and associations with dysregulated transforming growth factor-β. J. Vasc. Res. 2013, 50, 1–10.
    89. Schonherr, E.; Jarvelainen, H.T.; Sandell, L.J.; Wight, T.N. Effects of platelet-derived growth factor and transforming growth factor-β 1 on the synthesis of a large versican-like chondroitin sulfate proteoglycan by arterial smooth muscle cells. J. Biol. Chem. 1991, 266, 17640–17647.
    90. Wight, T.N. Arterial remodeling in vascular disease: A key role for hyaluronan and versican. Front. Biosci 2008, 13, 4933–4937.
    91. Yang, S.N.; Burch, M.L.; Tannock, L.R.; Evanko, S.; Osman, N.; Little, P.J. Transforming growth factor-β regulation of proteoglycan synthesis in vascular smooth muscle: Contribution to lipid binding and accelerated atherosclerosis in diabetes. J. Diabetes 2010, 2, 233–242.
    92. Rostam, M.A.; Kamato, D.; Piva, T.J.; Zheng, W.; Little, P.J.; Osman, N. The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle. Cell Signal. 2016, 28, 956–966.
    93. Kim, E.S.; Kim, M.S.; Moon, A. TGF-β-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int. J. Oncol. 2004, 25, 1375–1382.
    94. Safina, A.; Vandette, E.; Bakin, A.V. ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells. Oncogene 2007, 26, 2407–2422.
    95. Sinpitaksakul, S.N.; Pimkhaokham, A.; Sanchavanakit, N.; Pavasant, P. TGF-beta1 induced MMP-9 expression in HNSCC cell lines via Smad/MLCK pathway. Biochem. Biophys. Res. Commun. 2008, 371, 713–718.
    96. Cucoranu, I.; Clempus, R.; Dikalova, A.; Phelan, P.J.; Ariyan, S.; Dikalov, S.; Sorescu, D. NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ. Res. 2005, 97, 900–907.
    97. Samarakoon, R.; Overstreet, J.M.; Higgins, P.J. TGF-β signaling in tissue fibrosis: Redox controls, target genes and therapeutic opportunities. Cell Signal. 2013, 25, 264–268.
    98. Thallas-Bonke, V.; Jandeleit-Dahm, K.A.; Cooper, M.E. Nox-4 and progressive kidney disease. Curr. Opin. Nephrol. Hypertens. 2015, 24, 74–80.
    99. Jimenez-Altayo, F.; Meirelles, T.; Crosas-Molist, E.; Sorolla, M.A.; Del Blanco, D.G.; Lopez-Luque, J.; Mas-Stachurska, A.; Siegert, A.M.; Bonorino, F.; Barbera, L.; et al. Redox stress in Marfan syndrome: Dissecting the role of the NADPH oxidase NOX4 in aortic aneurysm. Free Radic. Biol. Med. 2018, 118, 44–58.
    100. Angelov, S.N.; Hu, J.H.; Wei, H.; Airhart, N.; Shi, M.; Dichek, D.A. 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.
    101. 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.; et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006, 312, 117–121.
    102. Cook, J.R.; Clayton, N.P.; Carta, L.; Galatioto, J.; Chiu, E.; Smaldone, S.; Nelson, C.A.; Cheng, S.H.; Wentworth, B.M.; Ramirez, F. 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. 2015, 35, 911–917.
    103. Huang, K.; Wang, Y.; Siu, K.L.; Zhang, Y.; Cai, H. Targeting feed-forward signaling of TGFbeta/NOX4/DHFR/eNOS uncoupling/TGFbeta axis with anti-TGFbeta and folic acid attenuates formation of aortic aneurysms: Novel mechanisms and therapeutics. Redox Biol. 2020, 38, 101757.
    104. MacFarlane, E.G.; Parker, S.J.; Shin, J.Y.; Ziegler, S.G.; Creamer, T.J.; Bagirzadeh, R.; Bedja, D.; Chen, Y.; Calderon, J.F.; Weissler, K.; et al. Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome. J. Clin. Investig. 2019, 129, 659–675.
    105. Holm, T.M.; Habashi, J.P.; Doyle, J.J.; Bedja, D.; Chen, Y.; van Erp, C.; Lindsay, M.E.; Kim, D.; Schoenhoff, F.; Cohn, R.D.; et al. Noncanonical TGFbeta signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science 2011, 332, 358.
    106. Shen, Y.H.; LeMaire, S.A.; Webb, N.R.; Cassis, L.A.; Daugherty, A.; Lu, H.S. Aortic Aneurysms and Dissections Series. Arterioscler. Thromb. Vasc. Biol. 2020, 40, e37–e46.
    107. Shen, Y.H.; LeMaire, S.A.; Webb, N.R.; Cassis, L.A.; Daugherty, A.; Lu, H.S. Aortic Aneurysms and Dissections Series: Part II: Dynamic Signaling Responses in Aortic Aneurysms and Dissections. Arterioscler. Thromb. Vasc. Biol. 2020, 40, e78–e86.
    108. van Dorst, D.C.H.; de Wagenaar, N.P.; van der Pluijm, I.; Roos-Hesselink, J.W.; Essers, J.; Danser, A.H.J. Transforming Growth Factor-β and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment. Cardiovasc. Drugs Ther. 2020.
    109. Huang, J.; Yamashiro, Y.; Papke, C.L.; Ikeda, Y.; Lin, Y.; Patel, M.; Inagami, T.; Le, V.P.; Wagenseil, J.E.; Yanagisawa, H. Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice. Sci. Transl. Med. 2013, 5, 183ra158.
    110. Gallo, E.M.; Loch, D.C.; Habashi, J.P.; Calderon, J.F.; Chen, Y.; Bedja, D.; van Erp, C.; Gerber, E.E.; Parker, S.J.; Sauls, K.; et al. Angiotensin II-dependent TGF-β signaling contributes to Loeys-Dietz syndrome vascular pathogenesis. J. Clin. Investig. 2014, 124, 448–460.
    111. 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.; et al. Impaired vascular contractility and aortic wall degeneration in fibulin-4 deficient mice: Effect of angiotensin II type 1 (AT1) receptor blockade. PLoS ONE 2011, 6, e23411.
    112. Xiong, W.; Meisinger, T.; Knispel, R.; Worth, J.M.; Baxter, B.T. MMP-2 regulates Erk1/2 phosphorylation and aortic dilatation in Marfan syndrome. Circ. Res. 2012, 110, e92–e101.
    113. Kuang, S.Q.; Geng, L.; Prakash, S.K.; Cao, J.M.; Guo, S.; Villamizar, C.; Kwartler, C.S.; Peters, A.M.; Brasier, A.R.; Milewicz, D.M. Aortic remodeling after transverse aortic constriction in mice is attenuated with AT1 receptor blockade. Arterioscler. Thromb. Vasc. Biol. 2013, 33, 2172–2179.
    114. Galatioto, J.; Caescu, C.I.; Hansen, J.; Cook, J.R.; Miramontes, I.; Iyengar, R.; Ramirez, F. Cell Type-Specific Contributions of the Angiotensin II Type 1a Receptor to Aorta Homeostasis and Aneurysmal Disease-Brief Report. Arterioscler. Thromb. Vasc. Biol. 2018, 38, 588–591.
    115. Chen, J.Z.; Sawada, H.; Moorleghen, J.J.; Franklin, M.K.; Howatt, D.A.; Sheppard, M.B.; Mullick, A.E.; Lu, H.S.; Daugherty, A. Inhibition of Angiotensin II Dependent AT1a Receptor Stimulation Attenuates Thoracic Aortic Pathology in Fibrillin-1C1041G/+Mice. bioRxiv 2020.
    116. Habashi, J.P.; Doyle, J.J.; Holm, T.M.; Aziz, H.; Schoenhoff, F.; Bedja, D.; Chen, Y.; Modiri, A.N.; Judge, D.P.; Dietz, H.C. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science 2011, 332, 361–365.
    117. Papakonstantinou, E.; Roth, M.; Kokkas, B.; Papadopoulos, C.; Karakiulakis, G. Losartan inhibits the angiotensin II-induced modifications on fibrinolysis and matrix deposition by primary human vascular smooth muscle cells. J. Cardiovasc. Pharmacol. 2001, 38, 715–728.
    118. Muino-Mosquera, L.; De Nobele, S.; Devos, D.; Campens, L.; De Paepe, A.; De Backer, J. Efficacy of losartan as add-on therapy to prevent aortic growth and ventricular dysfunction in patients with Marfan syndrome: A randomized, double-blind clinical trial. Acta Cardiol. 2017, 72, 616–624.
    119. Chiu, H.H.; Wu, M.H.; Wang, J.K.; Lu, C.W.; Chiu, S.N.; Chen, C.A.; Lin, M.T.; Hu, F.C. Losartan added to β-blockade therapy for aortic root dilation in Marfan syndrome: A randomized, open-label pilot study. Mayo Clin. Proc. 2013, 88, 271–276.
    120. Teixido-Tura, G.; Forteza, A.; Rodriguez-Palomares, J.; Gonzalez Mirelis, J.; Gutierrez, L.; Sanchez, V.; Ibanez, B.; Garcia-Dorado, D.; Evangelista, A. Losartan Versus Atenolol for Prevention of Aortic Dilation in Patients With Marfan Syndrome. J. Am. Coll Cardiol 2018, 72, 1613–1618.
    121. Li, L.; Yamani, N.; Al-Naimat, S.; Khurshid, A.; Usman, M.S. Role of losartan in prevention of aortic dilatation in Marfan syndrome: A systematic review and meta-analysis. Eur. J. Prev. Cardiol 2020, 27, 1447–1450.
    122. Jondeau, G.; Milleron, O.; Boileau, C. Marfan sartan saga, episode X. Eur. Heart J. 2020.
    123. Lacro, R.V.; Dietz, H.C.; Sleeper, L.A.; Yetman, A.T.; Bradley, T.J.; Colan, S.D.; Pearson, G.D.; Selamet Tierney, E.S.; Levine, J.C.; Atz, A.M.; et al. Atenolol versus losartan in children and young adults with Marfan’s syndrome. N. Engl. J. Med. 2014, 371, 2061–2071.
    124. Milleron, O.; Arnoult, F.; Ropers, J.; Aegerter, P.; Detaint, D.; Delorme, G.; Attias, D.; Tubach, F.; Dupuis-Girod, S.; Plauchu, H.; et al. Marfan Sartan: A randomized, double-blind, placebo-controlled trial. Eur. Heart J. 2015, 36, 2160–2166.
    125. Forteza, A.; Evangelista, A.; Sanchez, V.; Teixido-Tura, G.; Sanz, P.; Gutierrez, L.; Gracia, T.; Centeno, J.; Rodriguez-Palomares, J.; Rufilanchas, J.J.; et al. Efficacy of losartan vs. atenolol for the prevention of aortic dilation in Marfan syndrome: A randomized clinical trial. Eur. Heart J. 2016, 37, 978–985.
    126. Franken, R.; den Hartog, A.W.; Radonic, T.; Micha, D.; Maugeri, A.; van Dijk, F.S.; Meijers-Heijboer, H.E.; Timmermans, J.; Scholte, A.J.; van den Berg, M.P.; et al. Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome. Circ. Cardiovasc. Genet. 2015, 8, 383–388.
    127. Groenink, M.; den Hartog, A.W.; Franken, R.; Radonic, T.; de Waard, V.; Timmermans, J.; Scholte, A.J.; van den Berg, M.P.; Spijkerboer, A.M.; Marquering, H.A.; et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: A randomized controlled trial. Eur. Heart J. 2013, 34, 3491–3500.
    128. Milewicz, D.M.; Ramirez, F. Therapies for Thoracic Aortic Aneurysms and Acute Aortic Dissections. Arterioscler. Thromb. Vasc. Biol. 2019, 39, 126–136.
    129. Milewicz, D.M.; Prakash, S.K.; Ramirez, F. Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models. Annu. Rev. Med. 2017, 68, 51–67.
    130. Ford, C.M.; Li, S.; Pickering, J.G. Angiotensin II stimulates collagen synthesis in human vascular smooth muscle cells. Involvement of the AT(1) receptor, transforming growth factor-β, and tyrosine phosphorylation. Arterioscler. Thromb. Vasc. Biol. 1999, 19, 1843–1851.
    131. Che, Z.Q.; Gao, P.J.; Shen, W.L.; Fan, C.L.; Liu, J.J.; Zhu, D.L. Angiotensin II-stimulated collagen synthesis in aortic adventitial fibroblasts is mediated by connective tissue growth factor. Hypertens. Res. 2008, 31, 1233–1240.
    132. Milewicz, D.M.; Guo, D.C.; Tran-Fadulu, V.; Lafont, A.L.; Papke, C.L.; Inamoto, S.; Kwartler, C.S.; Pannu, H. Genetic basis of thoracic aortic aneurysms and dissections: Focus on smooth muscle cell contractile dysfunction. Annu. Rev. Genomics Hum. Genet. 2008, 9, 283–302.
    133. Muino-Mosquera, L.; De Backer, J. Angiotensin-II receptor blockade in Marfan syndrome. Lancet 2019, 394, 2206–2207.
    134. Abraham, H.M.; White, C.M.; White, W.B. The comparative efficacy and safety of the angiotensin receptor blockers in the management of hypertension and other cardiovascular diseases. Drug Saf. 2015, 38, 33–54.
    135. Nair, A.B.; Jacob, S. A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 2016, 7, 27–31.
    136. Mullen, M.; Jin, X.Y.; Child, A.; Stuart, A.G.; Dodd, M.; Aragon-Martin, J.A.; Gaze, D.; Kiotsekoglou, A.; Yuan, L.; Hu, J.; et al. Irbesartan in Marfan syndrome (AIMS): A double-blind, placebo-controlled randomised trial. Lancet 2019, 394, 2263–2270.
    137. Whelton, P.K.; Carey, R.M.; Aronow, W.S.; Casey, D.E., Jr.; Collins, K.J.; Dennison Himmelfarb, C.; DePalma, S.M.; Gidding, S.; Jamerson, K.A.; Jones, D.W.; et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 2018, 71, 2199–2269.
    138. van Andel, M.M.; Indrakusuma, R.; Jalalzadeh, H.; Balm, R.; Timmermans, J.; Scholte, A.J.; van den Berg, M.P.; Zwinderman, A.H.; Mulder, B.J.M.; de Waard, V.; et al. Long-term clinical outcomes of losartan in patients with Marfan syndrome: Follow-up of the multicentre randomized controlled COMPARE trial. Eur. Heart J. 2020, 41, 4181–4187.
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