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R EvI E W S

cellular and molecular mechanisms of thoracic aortic aneurysms
Ismail El-Hamamsyand Magdi H. Yacoub
abstract | Thoracic aortic aneurysms (TA A ) increase the risk of aortic dissection or rupture and represent an important source of morbidity and mortality. Inherited forms of the disease, including Marfan syndrome, have been recognized for a long time but were considered degenerative diseases characterized by cystic medial necrosis of the aortic wall. Improved definition of the structure and function of the normal aortic wall, coupled with the discovery of genetic mutations in key regulatory molecules, have contributed to a more detailed understanding of the pathophysiology of syndromic, familial and sporadic TAAs. We here review the cellular and molecular mechanisms involved in TA A formation and outline areas for future research.
El-Hamams I. & Yacoub, M. H. Nat. Rev. Cardiol. 6, 771–786 (2009); published online 3 November 2009; doi:10.1038/nrcardio.2009.1 91 y,

Introduction
traditionally, abdominal aortic aneurysms have been linked to atherosclerosis and steady progress has been made in understanding pathophysiological mechanisms under lying these aneurysms. By contrast, thoracic aortic aneu rysms (ta ) a have been labeled as a degenerative disease, characterized by cystic medial necrosis of unknown etio logy.1 this paradigm changed abruptly in 1991 with the discovery of a specific genetic locus encoding fibrillin 1, which is responsible for marfan syndrome, a condition characterized by the development of taas.2 this discov ery was followed by unprecedented activity in the field, with a rapid accumulation of landmark breakthroughs using genetic, molecular, cellular and engineering tech niques. Coupled with the use of targeted animal models, these discoveries are generating a much more cohesive unde rst anding of t he p at hogenesi s of taas, wit h extremely promising potential for clinical applications. the aortic wall is a highly dynamic and tightly regu lated structure that performs sophisticated functions in a unique hemodynamic environment. regulation of aortic wall homeostasis involves active mechanisms and inter actions between its major structural components and specific regulatory pathways. thus, a thorough under standing of the developmental origins of the thoracic aorta, its sophisticated structure and function, as well as factors that regulate them is fundamental for elucidating the pathophysiological mechanisms of taas. we here review the rapidly accumulating knowledge relating to these areas. mechanical properties of the aortic root and ascending aorta have a direct influence on left ventricular work load and coronary blood flow.3,4 studies have shown that a semirigid conduit (such as one made from Dacron®, invista, wichita, Ks, u a ) s originating from the heart significantly increases impedance, which translates into increased ventricular workload. 5–7 By contrast, intrinsic contractile properties, combined with the elastic recoil capacity of the ascending aorta optimize the shape and propagation of the pulse wave through the vasculature, an important determinant of the efficiency and distri bution of blood flow.8,9 active regulation of the size and shape of the aorta also has a direct effect on systemic blood volume and pressure. adequate function of the thoracic aorta is the result of a dynamic, tightly regulated and highly preserved microstructural organization of the aortic wall. all arterial walls have the same basic triple layer composition—intima, media and adventitia. these layers are separated from each other by two layers of thick elastic fibers, the internal and external elastic laminae. Depending on their location in the vascular tree, these layers vary considerably in thickness, composition and biological properties. the basic structural and functional unit in the aortic wall is the lamellar unit, first defined by wolinsky and

Harefield Heart Science

Aortic structure and function
the thoracic aorta performs several sophisticated func tions in addition to serving as a blood conduit origi

nating from the left ventricle. the unique shape and

competing interests The authors declare no competing interests.

Glagov.10 each lamellar unit is composed of a vascular smooth muscle cell (vsmC) sandwiched between two layers of elastin fibers, which contain microfibrils and proteoglycans that form the extracellular matrix (eCm; Figure 1). lamellar units are intercalated by collagen fibers. the lamellar unit has both tensile strength and elastic recoil properties, allowing the aorta to with stand high pressures and return to its initial diameter during diastole. the proximal conduction arteries have the highest number of elastic lamellae (55–60 u in the ascending aorta). 10 although the composition, thick ness (~15 μm) and tension (1–3 n/m) per lamellar unit is

Centre, The Magdi Yacoub Institute, Imperial College London, UK (i. El-Hamams y, M. H. yacoub). Correspondence: M. H. Yacoub, Harefield Heart Science Centre, Harefield Hospital, Hill End Road, Harefield, Middlesex UB9 6JH, UK m.yacoub@ imperial.ac.uk

nat r e rev ews | cardiolog u i | 771

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volume 6 | DeCem Ber 2009
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R EvI E W S
Key points
■ Developmental variations between the thoracic and abdominal aorta result in differences in cellular responses to similar biological stimuli ■ In addition to their structural role, the cells and proteins in the aortic wall have important regulatory functions that maintain homeostasis ■ Dysfunction of one or more components of the cytoskeleton–receptor– extracellular matrix complex can lead to structural and functional dysregulation of aortic wall properties ■ The transforming growth factor β1 pathway is important in matrix regulation in health and disease, and increased activity is a key component of various forms of thoracic aortic aneurysms (TAAs) ■ TAAs can be syndromic, familial nonsyndromic or sporadic, and are characterized by apoptosis and disarray of vascular smooth muscle cells, fragmentation of elastin, inflammatory infiltration, and upregulation of matrix metalloproteinases ■ Therapeutic strategies that target specific molecular pathways have shown promising results in mitigating TAA progression, and further understanding of the pathogenic mechanisms offers great potential for developing additional therapies

players in aortic wall homeostasis (cells, collagen, elastin

Elastin

EC M VSMC

Elastin

Figure 1 | The lamellar unit. Electron micrograph of a single lamellar unit in the medial layer of the aortic wall showing a vSMC lying between two layers of elastin fibers and surrounded by ECM proteins containing microfibrils and proteoglycans. Lamellar units are intercalated by collagen bundles. The lamellar unit represents the basic structural and functional unit of the aortic wall. Abbreviations: ECM, extracellular matrix; vSMC, vascular smooth muscle cell.

remarkably constant between the thoracic and abdomi nal aorta across species, notable differences have been observed in humans. the number of lamellar units in the ascending aorta ranges from 55–60 u and decreases to 28–32 u in the abdominal aorta.10 medial thickness in the ascending aorta is regulated by changes in the number of lamellae; in comparison, changes in lamellar thickness affect medial thickness in the abdominal aorta.11 studies by wolinsky and Glagov also suggest that the abdominal media is completely avascular, whereas the outer layers of the thoracic media contain vasa vasorum, which originate from the adventitia.11 interaction between the cellular and extracellular com ponents in the wall matrix mediates the various func tions of the aorta. Dysregulation of one or more of these components can pave the way for ta a formation. in the following sections, we present an overview of the major

elastin. All rights reserved s www. familial and sporadic). Gproteincoupled recep tors and the discoidin domain receptor family. therefore.and microfibrils). migration and alignment. these changes lead to the characteristic histological findings observed in taas. prob ably through loss of these direct feedback mechanisms that lead to loss of vsmC shape and alignment. Cell contraction. 16 importantly. alignment and repair of particular eCm components) that. fol lowed by a description of the main clinical presentations (syndromic. all of which are important elements in aortic wall homeo stasis. 23. leading to intracellular responses (cytoskeletal rearrangement and stress fiber alignment) and extracellular changes (synthesis.17–21 the fundamental unit of the cytoskeleton–cell receptor– eCm complex regulates the function of the aortic wall (Figure 2). can communicate directly with the cell.2 13. in addition to their contractile capacity. and abnormal signaling and synthesis of eCm proteins. vsmCs possess important secretory properties that ensure the synthesis and repair of various eCm components that regulate the structure of the vascular wall (collagen. 28 772 | DECEMBER 2009 | voluME 6 © 2009 Macmillan Publisher Limited. in turn. vsmCs can inter act directly with the different eCm components through cellsurface integrin receptors.24 two cytoskeletal gene muta tions have been linked to formation of nonsyndromic familial taas: smooth muscle cellspecific actin encoded by the ACTA2 gene on chromosome 10q2324.3 (table 1).22 mutations involving c ytoskeletal proteins in the vsmCs are involve d in taa for mat ion.21. fibrillin. contractile or proliferative states. these synthetic properties respond to biochemical signaling such as transforming growth factor β1 (tGFβ1). αactinin and filamin a. vsmCs are not terminally dif ferentiated cells—the y p oss ess b oth contractile and secretory properties and can alternate between quiescent. vsmCs can transform mechani cal stimuli into biological responses (also known as mechanotransduction).12–15 Contractions of vsmCs depend on the interaction between smooth muscle αactin and βmyosin heavy chain (βmHC). fibulin). vinculin. Key structural componentsof the aorta VSMcs the medial layer of the aorta is populated mainly by vsmCs. actin–myosin complexes in the cyto plasm are linked directly to the cell membrane through anchoring proteins such as talin.nature. as well the major regulatory pathways controlling aortic wall function in health and disease.25 and βmHC encoded by the MYH11 gene on chromosome 16p12. results in changes in cell shape. potential therapeutic strategies and future directions. or mechanical stimulation such as cellular strain.27 mutations in filamin a (an actinanchoring protein) have been associated with periventricular heterotopia and ehlers–Danlos syndrome with aortic aneurysms. and elastin fragmentation. including vsmC apoptosis and disarray. 26. which are circumferentially aligned and inter spaced by thin layers of elastic fibers. indeed.com/nrcardio .

29 they are found in the media and adventitia. and provide tensile strength and overall rigidity to the aorta. such as interleukin 2. . in addition to its structural role. it can interact directly with vsmCs through integrin receptors and elastinbinding protein to modulate cytoskeletal actin organization and limit cell proliferation and migration. lossoffunction mutations of one microfibrillar network components. vSMC. which is characterized histologically by vSMC disarray and elastin fragmentation. and regulates their local activity (Figure 3). which are two of the main similarly.25 and 4) the MYH11 gene. mutations in the COL3A1 gene encod ing type ii i collagen are associated with vasculartype ehlers–Danlos syndrome. mutations in genes encoding collagen fibers have direct structural and functional consequences that could contribute to ta a formation. vSMCs produce the various ECM components. encoding collagen III (Ehler–Danlos . shape. vascular smooth muscle cell. and their structural and signal ing characterized by unregulated vsmC properties have essential roles in health and disease. ECM proteins can directly interact with vSMCs by binding to cell-specific receptors (for example. type iv collagen is a component of the basement membrane of the tunica intima. vSMCs can sense mechanical stresses through specific membrane receptors and translate these stimuli into biological signals that are transmitted to the ECM (mechanotransduction).R EvI E W S collagen type i and type iii collagen are the most abundant colla gen fibers in the aortic wall.33. which is Figure 2 | The cytoskeleton–receptor–ECM complex. The receptors are linked directly to the cytoskeleton on the intracellular side.32 elastin is synthesized by vsmCs in the media in response to mechanical stimuli such as stretch or pressure. an autosomaldominant disorder characterized by taas (table 1). will focus on fibrillin and fibulin. Fibrillin mice deficient in elastin in addition to elastin and collagen—the major compo nents (Eln–/–) die soon after birth because of of the medial layer—microfibrils comprise a mosaic of severe occlu sive disease of the aorta. endo thelial cells adhere to and communicate with this layer. syndrome). and confers compliance and recoil capacity to the aorta. thereby directly affecting cell contraction. disruption of elastin signaling does not result in characterized by discrete stenosis in the aorta and other aneurysm forma tion or arterial dissection.36. migration and proliferation. 31 thus. in addition to its role in providing mechanical strength to the aortic wall. collagen acts as a reservoir for soluble factors. ECM regulation Cell alignment Adaptation of mechanics 1 2 ECM β α β α Cytoplasm Talin 3 4 Talin Vinculin Nucleus Elastin elastin is the dominant eCm protein in the aortic wall. elastin abnormalities result in an vsmCs despite normal endothelial function and the uncontrolled fibrocellular proliferative state absence of inflammatory or oxidative stimuli. arterial beds caused by subendothelial proliferation of instead. Fibrillins are extracellular elastin allele result in supravalvular microfibrils that interact with various stenosis and williams syndrome. encoding cytoskeletal actin (TAA4).26 Abbreviations: ECM. proteins in the eCm. collagen has several distinct functional properties. elastin has an active role in regulating the cellular components of the aortic wall.37 of vsmCs. encoding fibrillin 1 (Marfan syndrome) 2 2) the COL3A1gene. encoding β-myosin (TA A and patent ductus arteriosus). Thus.38 we 35 proliferation and fibrous deposition. extracellular matrix.109 3) the ACTA2 gene. In addition to their structural role. integrins and G-protein-coupled receptors). disruption to one or more elements of the cytoskeleton–receptor–ECM complex can affect aortic wall homeostasis and result in changes in the structure and mechanical properties of the aorta. Identified mutations that affect the cell–receptor–ECM complex and lead to aneurysms occur in 1) the FBN1 gene. In turn. constituting up to 50% of the dry weight of the thoracic aorta.30 moreover. in contrast to other eCm proteins. including activation of intracellular signaling cascades that affect cellular adhesion and proliferation by binding to cellsurface receptors. which highlights the regulatory role of this protein on vsmC proliferation. 13.34 elastin fragmentation is an almost ubiquitous finding in aneurysmal thoracic aortas but.

40 metabolically.eCm components such as elastin. are two isoforms that have been well described.48 and becomes less prominent in aortic wall homeostasis thereafter.42 Fibrillin 1 can also activate cell signaling pathways directly. compared with 1 mPa for elastin). Fibrillins 1 and 2. Fibrillin 3 has been described but its role in vascular physiology remains unknown. fibronectin and vitronectin. by binding to integrin receptors through the rGD motifs on fibril lins. respectively. collagen. which are encoded by genes on chromosomes 15 and 5. nat r e rev ews | cardiolog u i | 773 y volume 6 | DeCem Ber 2009 © 2009 Macmillan Publisher Limited. fibril lin 1 has a crucial role in the sequestration and regulation of the activity of growth factors and other microfibrillar proteins in the eCm.39 Fibrillin 1 is a major structural component that contributes to the mechanical strength of the aortic wall and forms a lattice surrounding elastic fibers (the Young’s modulus of microfibrils is estimated at 70 mPa. Figure 4). 43–47 the precise effect of vsmC– fibrillin inter actions remains unclear. such as tGFβ1 and bone morpho genic proteins (BmP. All rights reserved s . notably. Fibrillin 2 (along with fibrillin 1) is involved mainly in aortic morphogenesis during the fetal period. vascular anomalies are not associated with fibrillin 2 mutations. but they are thought to provide positional signaling to the cells. 41.

TG F -βR1 Type III collagen Notch 1 Unidentified GLUT10 Unidentified PTPN11 (SHP2) SOS1 G TPase K-Ras Unidentified Unidentified Polycystin 1 Polycystin 2 ECM Cell surface Cell surface ECM Intracellular Intracellular Unidentified Intracellular Cell membrane Cell membrane Cell membrane 123 2. 160–162 107.R EvI E W S Table 1 | Summary of the known syndromic and nonsyndromic familial forms of TAAs Taa classification chromosome gene Protein Syndromic Marfan syndrome Marfan-like syndrome Loeys–Dietz syndrome Ehlers–Danlos syndrome BAv–TA A syndrome Arterial tortuosity syndrome Turner syndrome Noonan syndrome 15q21. 121 118 122 location references Abbreviations: β-MHC.53 these changes have been linked to increased tGFβ1 activity (as shown by increased tGFβ1 expression and smad2 nuclear . 148. ECM. 49. son of sevenless homolog 1.50 mice that lack fibulin 5 expression demonstrate marked elastinopathy. T G F transforming growth factor β.1 2p21 -22 12p12. 49 Fibrillin 1 mutations are associated with marfan syndrome.1 Polycystic kidney disease Nonsyndromic TAAD1 FAA1 TAAD2 TAAD3 TAAD4 TAAD–patent ductus arteriosus TAAD5 5q13 -14 11q23 -24 3p24 -25 15q24 -26 10q23 -24 16p12 -13 9q33 -34 Unidentified Unidentified TGFBR2 Unidentified ACTA2 MYH11 TGFBR1 Unidentified Unidentified TG F -βR2 Unidentified Smooth muscle actin β-MHC TG F -βR1 Unidentified Unidentified Cell surface Unidentified Intracellular Intracellular Cell surface 130 131 83. 144. 108 80. TGF-βR. character ized by aortic tortuosity. TGFBR1 COL3A1 NOTCH1 Unidentified SLC2A10 Unidentified PTPN11 SOS1 KRAS PKD1 PKD2 Fibrillin 1 TG F -βR2 TG F -βR2. β-myosin heavy chain. 116 114. 99.3 -31 9q34 -35.1 3p24 -25 3p24 -25 9q33 -34 2q24.1 45. solute carrier family 2. others 20q13. 111 57. glucose transporter type 10. 27 125 16p13. fibulins are active metabolic regulators of aortic wall homeostasis. Notch 1. neurogenic locus Notch homolog protein 1. 115. mice homozygous for a lowexpres sion allele of fibulin 4 show dilatation of the ascending aorta as well as aortic tortuosity and stiffening caused by disorganized elastic fiber deposition. TA AD.3 4q21 -22 FBN1 TGFBR2 TGFBR2 . 163 120. extracellular matrix. tyrosine-protein phosphatase non-receptor 11. 52 Fibulin 4 has been linked to regulation of the struc tural integrity of the vascular wall through modulation of tGFβ1 activity. Fibulin as with other eCm proteins. GLUT10. SLC2A10. transforming growth factor β receptor. TAA. Fibulin 5 acts as a scaffold for the deposition of elastic fibers in the matrix and has an essential role in formation of the lamellar unit by linking elastin to vsmCs. suggesting that fibrillins have welldefined tissuespecific roles.X0 12q24. thoracic aortic aneurysm. 112. -β. 140 132 25 26. 81 81 109. SOS1. thoracic aortic aneurysms and dissections. 51 Patients with fibulin 5 mutations present with the typical association of cutis laxa and lung emphysema (no aortic dilations have been described in humans). facilitated glucose transporter member 10. as discussed later (table 1). loose skin and emphysematous lungs. PTN11.

skin features are rather mild and lung emphysema is not pronounced. on the other hand. Further work is required to fully elucidate the regulatory role of fibulins. unlike fibulin 5 mutations. During the early stages of embryonic development. inc luding in vascular morphogenesis. is mainly composed of mesodermderived cells (Figure 5). Major regulato pathways ry ontological regulation most of the signals that are operational during morpho genesis continue to influence growth and adaptation in postnatal life.com/nrcardio . 55. as well as some skeletal fea tures such as joint hypermobility. defining the developmental biology of the thoracic aorta has important implications for understanding normal and diseased aortic wall physio logy.translocation) and upregulation of matrix metallopro teinase (mm P) 9 expression. the abdominal aorta.nature.53 Fibulin 4 mutations in humans present predominantly as aortic and arterial aneurysms and tortuosity.54 However.56 Formation of vsmCs further depends 774 | DECEMBER 2009 | voluME 6 © 2009 Macmillan Publisher Limited. the aortic valve and the ductus arteriosus. All rights reserved s www. migration and differentiation of cells from the neural crest give rise to the ascending aorta. thus.

R EvI E W S on local epithelial–mesenchymal transformation (e t ). Mutations in collagen fibers such as observed in type Iv Ehler– Danlos syndrome can affect both the structure and the function of the aortic wall.65 although aneurysmal aortic specimens show reduced collagen in areas of dilatation. 58 Differences were also observed in proliferation and signal transduction pathways.62–64 atherosclerosis resistant ascending aortic segments were substituted with atherosclerosisprone abdominal aortic segments in dogs that were subsequently fed an atherogenic diet for 1 year. characterized by changes in cell alignment. Abbreviations: ECM. proliferation and synthesis. the atherosclerosisprone abdominal aortic segments developed severe atherosclerotic lesions. thus. IL-2. BMP. Collagen 1 Structural integrity 3 Sequestering soluble ECM cytokines 2 4 Interaction with ECM proteins Activation of signaling cascades Talin Vinculin Figure 3 | Illustration of the roles of collagen fibers in the ECM. including radial strain and wall shear stress from the flow of blood. these findings. these features of the thoracic aorta were originally demonstrated in a series of early studies looking at the role of the intrinsic properties of the aorta in disease initiation and progression. whereas parallel stimulation of mesodermderived vsmCs did not have the same effect. Fibrillin 1 Structural integrity Aortic morphogenesis Binding of various ECM proteins (LTBP. vascular smooth muscle cell. after this period. In vitro studies have shown the ability of cul tured vsmCs to respond to stretch by changing their proliferative rate and increasing collagen production. vSMC. migration. vsmCs grown in culture show lineagedependent differences in growth and receptormediated transcriptional responses to tGFβ1. thereby regulating their function. and expression of matrix and cytoskeletal proteins. activation of the protein kinase C signal ing pathway and collagen production. these various studies show that tGFβ1 stimulation of neuralcrestderived vsmCs resulted in a significant increase in Dna synthesis.59 integrin expression and 60 collagen interactions. Collagen fibers provide 1) structural strength to the aortic wall and have the following additional functions: 2) direct interaction with vSMCs and activation of different intracellular signaling pathways. decorin) Direct interaction with cell receptors Fibrillin-1 mutations Mechanical regulation the thoracic aorta is exposed to a variety of mechani cal stresses during each cardiac cycle. 3) reservoirs for soluble enzymes and cytokines in the ECM. combined with the struc tural differences between the thoracic and abdominal lamellar units. highlight the regional heterogeneity within the aorta and the singular properties of the thoracic aorta described earlier. whereas the ascending aortic homograft in the abdomi nal position failed to develop intimal lesions. these mechanical cues have a direct effect on structure and function of cells in the aortic wall. cell proliferation. 4) interaction with other ECM proteins to regulate their function. extracellular matrix. this Stiffening of the aortic wall Increased T G F β1 activity ■ In ammation ■ MMP upregulation ■ Elastolysis ■ Cell disarray could be attributed to . m a process regulated by specific molecular pathways.61 indeed. interleukin 2. including the tGF–β1 and notch 1 signaling pathways. suggesting that intrinsic properties were at least as important as environmental factors that are thought to be operative in the pathogenesis of disease.57 Differences in cell lineage translate into different cellu lar responses to similar stimuli.

fibrillin 1 is an important structural component of the aortic wall. increased bioavailability and activity of T G F -β1. vascular smooth muscle cell. T G F -β1. which will be considered in more detail later in the review. compared with other areas of the ascending aorta. ECM. Mutations in the fibrillin 1-encoding gene lead to structural changes in the aorta. the role of local mechanical stresses on the aorta have been specifically investigated by Della Corte et al. All rights reserved s . a process mediated by mm Ps.. forming a lattice around elastic fibers.159 These changes result in elastin fragmentation. fibrillin 1 can interact 45–47 even higher levels of concomitant proteolysis. extracellular matrix. vSMC. MMP. bone morphogenic proteins.40 Fibrillin 1 is also involved in aortic morphogenesis during the fetal period. who showed a regional pattern of vsmC apoptosis in ascending aortas associated with bicuspid aortic valve (Bav) disease. content and composition. matrix metalloproteinase. latent T G F -β1binding protein.23 vsmC apoptosis was significantly increased at the aortic convexity (the site of highest stresses). Abbreviations: BMP. chemotaxis. In normal individuals. in conjunction with fibrillin 2. LTBP. 86.106.66 these studies demonstrate the importance of the local mechanical environment and the role of activated mechanotransduction pathways nat r e rev ews | cardiolog u i | 775 y volume 6 | DeCem Ber 2009 © 2009 Macmillan Publisher Limited.96. transforming growth factor β1.Figure 4 | The structural and functional effects of normal and mutant fibrillin 1 in the regulation of aortic wall homeostasis. inflammation and expression of MMPs.23 these changes occurred in parallel with a similar regional heterogeneity in matrix protein directly with integrin receptors on vSMCs. cell apoptosis and disarray.41. 48 and has pivotal regulatory functions by sequestering cytokines and growth factors such as T G F -β1 through binding to LTBP.42 Although its functional effect remains unknown.

as dila tation occurs. in practice. RC A. a large molecule that keeps tGFβ1 in an inactive state in the matrix (Figure 6). wall shear stress is the main mechanical stimulus for endothelial cells lining the aortic wall. pulmonary trunk. the bioavailability of active tGFβ1 in the eCm is more dependent on protease activity than on de novo synthesis. the role of shear stress has been thoroughly studied. can directly cleave the ltBP–laP complex. ascending aorta. INN. transmural strain increases with increases in radial diameter. LCA and R CA. LCA. Development 127. contractile or synthetic properties. RCA LCA LS CA RS CA INN aAo PT dAo Figure 5 | Developmental origin of cells populating the ascending aorta.67 initially. INN. particularly as a factor contributing to the development of athero sclerosis in areas of low shear (curvatures or bifurca tions). leading to a change in proliferative. LSCA. PT. or on direct cellsurface binding of the llC to integrins. in addition. according to laplace’s law. right subclavian artery. other signals capable of cleaving laP–tGFβ1 bonds include thrombospondin 1 (tsP1). but only a fraction of it is metabolically active. in the eCm. leading to matrix degradation through increased production of plasminogen activators and release of mm Ps 2 and 9 in the matrix.42 activation of tGFβ1 depends either on the release of ltBP from the microfibrils. and inversely propor tional to the third power of the internal radius.69 tGFβ1 is now recognized as a key com ponent in the pathogenesis of taas. shear stress—the frictional force per unit area—is proportional to blood viscosity and volumetric flow rate. which can be found independently in the matrix in mutated forms of the protein.left subclavian artery. allowing cleavage of the laP– tGFβ1 bond. aAo. tGFβ1 was thought to con tribute solely to matrix synthesis through stimulation of . the pattern and magnitude of shear can vary significantly along its surface. RSCA. these changes are expected to become more pronounced as the aorta increases in size and therefore contribute to the observed vsmC apop tosis and disarray. Neural crest cells are LacZ-positive (blue). Abbreviations: aAo. although the ascending aorta is often perceived as a tubular structure with high shear stresses. the large latent complex (l C) containing tGFβ1 is bound l to the latent tGFβ1binding protein (ltBP). The LSCA and the dAo beyond the ductus arteriosus (which is also derived from neural crest cells) are not derived from the neural crest. reduced or mutated forms of fibrillin 1 stimulate release of sequestered tGFβ1 and an increase in its activity. 68. However. Permission obtained from The Company of Biologists © Jiang et al. ltBP–llC or regulation through biochemical signaling TG F -β1 tGFβ1. in mediating cellular and matrix responses. Fibrillin 1 acts as potent regulator of tGFβ1 bioavailability by binding to ltBP (Figure 6). dAo. these changes can translate into altered paracrine signaling from endo thelial cells to underlying vsmCs. 71 the data now reveal a prominent opposing role of tGFβ1. which in turn can activate the smad and the p38 mitogenactivated protein kinase (m PK) a pathways in vsmCs. 1607–1616 (2000). a member of a large family of cytokines that includes activins and BmP. fragments of fibrillin 1 (PF10).R EvI E W S collagen and elastin production. as well as matrix protein degradation in taas. has a central role in cardiac an d vascular morphogenesis and in maintaining eCm homeostasis. left carotid artery.70 Consequently. tGFβ1 is present in normal aortic walls. innominate artery. descending aorta.right carotid artery. releasing active tGFβ1. Notice the distribution of neural crest cells to the aortic root.

smad2/3 signaling in the absence of smad4 involvement and activation of smads 2 and 3 by other signaling mediators in response to tGFβ1. inhibits tGFβ1 signaling by binding to the tGFβ propeptide and preventing its maturation in the extracellular space.41. including the loeys–Dietz syn drome (lDs) 81 and a familial nonsyndromic form of ta (ta 2.72–75 By contrast.76 Emilin1knockout mice present with hypertension (an effect attributed to increased tGFβ1 activity) 76 and show alterations in cell morphology and elastic fibers in the aortic wall.BmP1. including direct stimula tion of tGFβr2 without tGFβr1 activation. changes in local pH and various proteases.78.79 these alternative pathways help to explain the formation of taas in individuals with mutations in tGFβr1 and tGFβr2. it binds to tGFβ receptor (tGFβr) 2. starting with receptorassociated smads (smads 2 and 3 or rsmad) that associate with a cosmad (smad4). once active tGFβ1 is free in the matrix.80–83 mutations in tGFβ receptors have been linked to several condi tions leading to taas. alternative tGFβ1 signaling path ways have also been proposed. emilin 1.nature. activation of tGFβr1 without smad signaling. translocating to the nucleus and inducing specific gene activators or repressors (Figure 6).77 the role of emilin 1 in the pathogenesis of human taas remains to be defined. which paradoxically show histological signs of tGFβ1 overactivity.com/nrcardio . which in turn recruits and activates tGFβr1. All rights reserved s www. table 1). a matrix glycoprotein. 83 a a 776 | DECEMBER 2009 | voluME 6 © 2009 Macmillan Publisher Limited. inducing a signaling cascade of intra cellular signaling protein phosphorylation.

as well as direct binding to tim Ps. including resident cells (vsmCs and fibroblasts) and inflammatory cells (neutrophils and macrophages). matrix proteolysis is one of the hallmarks of taas.94. whereas tim Ps are endogen ous inhibitors that act directly by binding to and inactivating mm Ps.95 possibly reflecting spatiotemporal heterogeneity between studied samples. this expression profile is followed by a decrease in tim P1 expression once Bav–taas . However. mm P expression rather than activity is usually examined and few studies have focused specifically on syndromic or familial forms of taas (with TSP1 FBN fragments MMPs LLC Emilin 1 Inactive T G F β1 T G Fβ LAP LTBP Fibrillin 1 T G Fβ TG Fβ ECM Matrix proteolysis Active T G F β1 MMP2 TGF β TGF β MMP9 R2 R1 R2 R2 P R1 P Smad2/3 P SLC Smad2/3 Cytoplasm P Smad2/3 Nucleus the exception of those associated with marfan syndrome and Bavs). along with a decrease in mm P3 and mm P14 expression.R EvI E W S MMPs mm Ps and their tissue inhibitors (timPs) constitute a series of zinccontaining enzymes capable of matrix degradation. thus preventing excessive matrix degradation. taa diameters at the time of harvest are vari able. possibly suggesting different mecha nistic pathways. nevertheless. matrix degradation products or increased tGFβ1 activity.85. familial or sporadic taas. various studies have examined the mm P profile in explanted thoracic aortas from patients with syndro mic.86 mm Ps cause eCm degradation mainly through direct proteolysis of its structural com ponents. Factors such as members of the m PK pathway and the nuclear factor κB a (nFκB) signaling pathway can regulate mm P transcription. 91.87 the metabolic activity of mm Ps in the matrix is mitigated through sequestra tion by eCm proteins. an accurate description of diseasespecific changes remains difficult because of a lack of uniformity between study protocols: aortic har vesting sites var y between studies. taas associated with Bavs are characterized by an increase in mm P2 expression.69.93 mm P2 expression is increased in Bav–taas ranging from 4–6 cm.88–90 these studies show marked hetero geneity in mm P expression profiles between different taa etiologies. further showing that mm P14 activity is decreased in Bav aortas (mm P14 is an activator of mm P2). 93 the authors also showed changes in mm P expression according to aortic size. several important elements are apparent. performed a complete analysis of protease expression in this patient population. remodeling and processing of eCm proteins and adhesion molecules. in response to inflammation. 84. oxida tive stresses. ikonomidis et al.85 mm Ps can be produced by many cell types. the main regulatory step of mm P expression and activity occurs at the transcriptional level (a notable exception is mm P2). increas ed mm P expression is consistently obs er ved in ta a specimens. the local balance between mm Ps and tim Ps determines the overall effect on aortic wall matrix composition.85 Posttranscriptional and posttranslational controls have also been identified in the regulation of mm P activity. resulting in regional variations in mm P expression along the circum ference. whereas healthy aortic tissue shows little expression of mm Ps. 89–94 mm P9 expression was inconsis tently increased in Bav–taas.

FBN fragments and changes in pH can cleave the LA P –T G-β1 or the LTBP–LLCbonds. MMP. transforming growth factor β1. large latent complex. ikonomidis et al. stabilizing T G F in an -β1 inactive state. thus F releasing active T G F -β1 in the matrix. T G F -β1. TSP1. compared with controls. LAP. In addition. for taas associ ated with tricuspid aortic valves. extracellular matrix. large latent T G F -β-binding protein. 89 a recent analysis of taas from a nat r e rev ews | cardiolog u i | 777 y volume 6 | DeCem Ber 2009 © 2009 Macmillan Publisher Limited. forming the LLC. mutations in TGFBR 1and TGFBR2 result in increased T G F activity. This complex interacts with ECM components including fibrillin 1 through LTBP. fibrillin 1. The traditional T G F -β1 signaling pathway requires binding to T G F -βR2. By contrast. which in turn binds to the LTBP. TG F -βR. FBN. LTBP. Finally. Increased T G F activity leads to matrix -β1 proteolysis through release of proteases including MMP2 and MMP9.Figure 6 | The role of T G F in TA A formation. All rights reserved s . showed that mmP14 and timP2 were increased in taas associated with marfan syndrome. matrix metalloproteinase. compared with agematched nonmarfan syndrome taas. exceed 6 cm in diameter. recruitment of T G F -βR1 and a series of Smad protein phosphorylations leading to nuclear translocation of the Smad2–Smad3 complex and specific gene activation or repression. this represents the main step in regulating its activity. which might represent an important mechanism of mm P activity regulation. few studies have examined changes in protease expression in patients with marfan syndrome. latency. a gene array study on taa samples from patients with bicuspid or tricuspid aortic valves showed down regulation of metallothioneins in taas. thrombospondin 1.95 the precise role of metallothioneins is not yet fully understood but they are thought to affect mm P expression in the aortic wall. Alternative T G F -β1 -β1 signaling pathways such as direct stimulation of T G F -βR2 without T G F -βR1 activation have been proposed. an initial decrease in timP2 expression (<4 cm in diameter) is followed by a late increase in mm P7 expression (>6 cm). Abbreviations: ECM. and reduced metallothionein production by cultured vsmCs from diseased aortas. various proteases. transforming growth factor β receptor. T G F is -β1 -β1 normally maintained in an inactive state in the ECM by binding to the LAP. LLC. TSP1.associated peptide.

par ticularly in the adventitia. with a on inflammatory and oxidative pathways. Permission obtained from Nature Publishing Group © Zhao et al. leading to recruitment of T-cells in the adventitia (2).101 expression of mm Ps 2 and 9 was also decreased. which cause matrix degradation. matrix metalloproteinase. given its promising therapeutic implications. 966–973 (2004). macrophage inflammatory protein. as well as induce vsmC apoptosis. 96 inflammation and oxidative stress Histological analysis of taas often shows the presence of inflammatory cells in the adventitia and media of the aortic wall. leukotriene D4. Zhao et al. 100 mice deficient for the cyclophilin a protein were completely protected from aneurysm formation. LTD4 also stimulates production of MIP2 by endothelial cells in the vasa vasorum (3).g. particularly in sporadic cases of the disease. CD45 + and CD68 + cells).101 these studies underscore the need for further research into the pathogenesis of sporadic taas. which leads to leukocyte recruitment in the adventitia (4). compared with normal controls. 10.R EvI E W S taas consistently show the presence of inflammatory and immune cells (CD3 +. showed that macrophagedependent inflammation in the adven titia has a direct role in the pathogenesis of aortic aneu rysms (albeit abdominal aneurysms). along with an increase in the density of the vasa vasorum and local endothelial activa tion (as observed in Figure 8). this phenomenon suggests that inflammatory pathways might play an important part in the regulation of aortic wall physiology.98. Nat. resulting in aortic wall weakening and elastolysis. MMP. inhibition of the stress activated protein kinase Jun aminoterminal kinase (JnK) in two mouse models of abdominal aneurysms resulted in prevention of aortic dilatation and medial thinning. a study of abdomi nal aortic aneurysms has demonstrated the central role of cyclophilin a (a chaperone protein that binds cyclosporin and is abundantly expressed in vsmCs) in disease patho genesis. adventitia expressed 5lipoxygenase and mediated their negative effects mainly through activation of endothelial cells lining the vasa vasorum and release of mm P2 in the aortic wall (Figure 7).97 in that study. oxidative stress has long been implicated in the pathogenesis of abdomi nal aneurysms. However. Cells accumulating in a 5-LO-dependenttissue can release proteases such as MMP2 (5). with the adventitia as the epicenter of patho genesis of the disease. histological analyses of aortic wall specimens from patients with familial or sporadic Endothelial cell Blood vessel lumen Macrophage Elastin Smooth muscle cell Intima Media Macrophage 6 5-LO CysLT1 R LTD 4 1 2 MIP1 α 5-LO ECM-degrading factors (e. Med. suggesting an ‘outsidein’ theory of aneurysm formation. in addition to inflammatory pathways. 97 Crossing 5lipoxygenasenull mice with apoe–/– mice resulted in a significant reduction in aneur ysm for mation. MMP2) 5 Adventitia 3 CysLT2R LTD4 4 MIP2 Aneurysm granuloma T cells Monocyte Endothelial cells of vasa vasorum Figure 7 | The ‘outside-in’ theory showing the role of the 5-LO pathway in the formation of aortic aneurysms. reactive oxygen species can increase the expression and activity of mm Ps. 24. the link between oxidative stress and taa formation remains to be firmly established. particular focus mouse model of marfan syndrome shows an increase in mm P2 and mm P9 expression and a timedependent increase in the mm P2:timP2 ratio. an interesting new paradigm in the understanding of isolated aneurysms has been proposed. and preservation of aortic wall architecture. emphasizi ng its crucial role in ‘degenerative’ aneurysms. interestingly. Abbreviations: 5-LO. highlighting its central role in mediating matrix degra dation.97 macrophages and CD3 + cells in the . LTD4.99 no studies have yet linked 5lipoxygenase activity or other specific inflam matory pathways with taa formation but further work is warranted. MIP. 100 in a separate study. 5-lipoxygenase. LTD4 stimulates the production of MIP1α by macrophages in an autocrine fashion (1).

multi system disorder with manifestations typically involving the cardiovascular. All rights reserved s www. particularly in rela tion to the exact mechanisms of different manifestations or complications of the disease in individual patients. Marfan syndrome marfan syndrome is an autosomaldominant. Diagnosis is based on a specific set of criteria that take into account all potentially involved systems. taas are a main feature of some syndromes. this clinical classification has facilitated the identifica tion of a large number of genes responsible for syndro mic forms of taas and some of the genes associated with familial taas. in other cases. namely marfan syndrome. skeletal and ocular systems. such as Bav syndrome and turner syndrome. loeys–Dietz and ehler–Danlos syndrome. Classification of taas has also been useful in elucidating the underlying mechanisms. there are still several gaps in our knowledge. familial or sporadic.com/nrcardio .nature. However.102 marfan syndrome Syndromic Taas syndromic taas are defined as aneurysms that occur in conjunction with a range of associated anomalies affecting 778 | DECEMBER 2009 | voluME 6 © 2009 Macmillan Publisher Limited.Clinical classificationof TAAs taas are classified as syndromic. taas are a possible manifestation. various body systems.

elastin fragmentation and increased inflammatory infiltration (particularly in the adventitia) characterized by the presence of CD45+ (leukocytes). Abbreviations: NFκB. vascular smooth muscle cell.105 a second locus linked to chromosome 3p2425 has been identified and a marfanlike syndrome described.104 the changes observed were attributed to a marked increase in tGFβ1 activity and signaling. leading to aneurysm formation.41. suggesting that the develop mental problems result from altered cell behavior during morphogenesis. thoracic aortic aneurysm. 105 treatment of mutant mice with systemic tGFβ1neutralizing anti bodies reversed the pulmonary parenchymal changes in vivo.80 uncertainty also remains as to how well these patients were evaluated for features of loeys–Dietz syndrome. which result from active changes in cell function. vSMC. such as the skin and uvula abnormalities. macrophage chemot axis and inflammation. highlighting the crucial role of fibrillin 1 in regulating the tGFβ1 pathway. elastin fragmentation. such as bone overgrowth and mitral valve anomalies. since the first mutation in this gene was described in 1991.107 this locus is associated with the gene encoding tGFβr2. CD68+ (macrophages)and NFκB+ cells.108 Controversy persists as to whether these individuals have pure marfan syndrome. as mutations in TGFBR1 and . smooth muscle actin. TAA.86.104 as well as the mitral valve anomalies.82. nuclear factor κB. analyses in newborn mice with fibrillin 1 mutations showed abnormal sep tation of the distal alveoli. including increased mm P signaling. SMA.000 different (mostly missense) mutations have been identified. Typical findings include vSMC disarray. as they presented with some atypical features such as cervical spine instability. patent ductus arteriosus and cardiac septal defects. However. compared with a normal aortic wall obtained from a transplant recipient with a normal aorta.2 more than 1.R EvI E W S SMA Elastin CD45 CD68 N FκB Figure 8 | Typical immunohistochemical findings in an explanted aortic wall of a patient who underwent surgery for a nonfamilial TA A. vsmC apoptosis. results from mutations in the fibrillin 1 gene located on chromosome 15q1531.106 tGFβ1 activity also explains the associated manifestations in marfan syndrome.103 the decrease in structural fibrillin 1 was originally thought to result directly in weakening of the aortic wall. increased tGFβ1 activity and products of fibrillin 1 degradation together lead to the observed histological findings in aortas of patients with marfan syndrome.

mutations in TGFBR1 and TGFBR2 have been linked to the syndrome. mutations in the fibrillin 2 gene have not been linked to vascular diseases. connective tissue growth factor and increased nuclear phosphorylation of smad2. cells obtained from the aortic wall of patients with loeys–Dietz syndrome have increased collagen.81 Patients with this syndrome present with aortic dissection at a young age and with aortic diameters less than 5 cm. the precise mechanisms for increased tGFβ1 signaling remain poorly understood as mutations in the kinase domain are expected to reduce signal transduction. most mutations are mis sense mutations that commonly affect an intracellular kinase domain on the receptor. craniosynostosis. Paradoxically. reducing receptor signal ing activity in response to tGFβ1. indicating that tGFβ1 activity is increased. trans lucent skin.81 thus. the natural history of the disorder differs con siderably from that of other connective tissue disorders. as well as a familial form of nonsyndromic taas (ta 2). alternative signaling pathways are probably activated but have not yet been clearly defined. bifid uvula. cleft palate and thin. All rights reserved s . a as will be discussed later. arterial aneurysms and dissection. highlighting the central role of increased and dysregulated tGFβ1 signaling in aneu rysm formation.80 the median age for occurrence of a first major vascular event in loeys–Dietz syndrome is 30 years. Loeys–Dietzsyndrome loeys–Dietz syndrome is an autosomaldominant disorder characterized by taas. the same putative mechanism of increased tGFβ1 activity invoked in marfan syndrome is also at play in loeys–Diet z syndrome. there are no apparent differences in the clinical presentation between patients with TGFBR1 or TGFBR2 mutations. to date. nat r e rev ews | cardiolog u i | 779 y volume 6 | DeCem Ber 2009 © 2009 Macmillan Publisher Limited. o verall. 80.TGFBR2 genes have been associated with this syndrome. of note.

which counteract the r effects of excessive tGFβ1 signaling. Ehlers–Danlossyndrome vascular ehlers–Danlos syndrome (type iv) is an auto somaldominant disorder that manifests with arterial aneurysms. consider ing the role of notch 1 signaling in valvular and vascular morphogenesis.110 respectively.109 BAV syndrome Bav disease is the most common cardiovascular mal formation in humans (1– 2%). 114 supports the notion that Bav and taa can occur independently in individuals from Bav families. trans lucent skin and easy bruising.111 more than 70 different mutations have been identified in patients with the disease. treatment with angiotensinreceptor blockers (a Bs). Bav syndrome can manifest with various left heart lesions such as hypoplastic left hearts.115 no specific mutation has yet been associated with the combined Bav–taa phenotype although evidence now suggests that NOTCH1 mutations might be involved in a subset of patients with combined Bav and ta .80 compared with 48 years and 70 years for patients with type iv ehler–Danlos syndrome109 and actively treated mFs.117 Turner syndrome turner syndrome is characterized by a 45. in addition to bicuspid valve abnormalitites. patients with type iv ehler–Danlos syndrome are at a greater risk of adverse outcomes follow ing vascular surgery than are patients with other connective tissue disorders. 113 the finding that firstdegree relatives of patients with Bavs have a 32% incidence of aortic root dilatation. particularly in guiding neural crest cell migration and e t. as well as thin.109. median survival of patients with vascular ehlers–Danlos syndrome is estimated to be 48 years. its phenotypic characteristics .R EvI E W S with a median survival of patients with loeys–Dietz syn drome of 37 years. as suggested by a study showing increased tGFβ1 expression and nuclear translocation of smad2. a study of 13 families of probands present ing with combined Bav and ta a strongly suggests that Bav–taa syndrome follows an autosomaldominant p attern of inheritance.116 this a observation is interesting.Xo aneuploid chromosomal constitution. arch hypo plasia and aortic coarctation.57 m increased tGFβ1 activity might also contribute to aneurysm formation in patients with Bavs.109 Diagnosis is confirmed by demonstration of abnormal production of type iii pro collagen by cultured fibroblasts or by genetic screening. Given the extreme friability and fragility of aortic tissue. despite having normal tricuspid valves. is of benefit to patients with marfan syndrome. which encodes type iii collagen. rupture and dissection.112 taas affect about 40% of patients with Bavs and are thought to be associated with increased risk of dissection and rupture.109 type iv ehlers–Danlos syndrome results from mutations in the COL3A1 gene. and is likely to benefit patient with loeys– Dietz syndrome but studies have yet to confirm whether a B treatment will be r successful in this condition.

about 10–30% of familial a nonsyndromic taas). including noonan syn drome122 and polycystic kidney disease123 show features of aortic aneurysms (table 1). Arterial tortuosity syndrome we have previously encountered individual cases of arte rial tortuosity associated with thoracic aneurysms and areas of arterial narrowing. 130 11q23. gonadal disgenesis.119 arterial tortuosity syn drome has been described as an autosomalrecessive dis order characterized by tortuosity. an elongated face. a patent ductus Familial nonsyndromic Taas the existence of familial but nonsyndromic taas was recognized in the 1980s. and the mechanisms remain unknown. However. 133 ACTA2 mutations ACTA2 mutations were first identified in a large family affected by nonsyndromic taas that have an autosomal dominant inheritance mode and decreased penetrance (ta 4). downslanting palpebral fissures and a beaked nose. have been linked to the syn drome. with decreased pene trance (especially in female family members) and variable expression.125. 25 in addition to taas. coarctation of the aorta. ACTA2 in ta 4 and MYH11 in a a familial ta a and patent ductus arteriosus.120. Other syndromes several other genetic syndromes. All rights reserved s www. the remaining loci are 5q1314 (ta 1. which encodes the facilitative glucose transporter Glut10.com/nrcardio .124 these taas occur as a single 780 | DECEMBER 2009 | voluME 6 © 2009 Macmillan Publisher Limited. often autosomal dominant. a less than 5% of familial nonsyndromic taas) 131 and 15q24 26 (ta 3. web neck and widely spaced nipples.120 associated features inc lude micrognathia. 132 studies to identify the specific genes involved in the pathogenesis of these different taas are in progress. the incidence of taas in these syndromes is significantly lower than those described above.nature. which are present in almost 40% of patients with turner syndrome.118 little is known about the pathological features of aortas from patients with the syndrome.127– 129 six different genetic loci have been recognized in families with familial nonsyndromic taas (table 1). elongation. manifestation. associated cardiovascular anoma lies include Bav.121 extended followup of affected individuals and increased awareness and recogn ition of this syn drome will increase understanding of the clinical course of associated taas. but follow a familial pattern of inheri tance. iris f loculi.126 the incidence of taas in firstdegree relatives of patients with isolated taas is 11–19%. about a 10–20% of familial nonsyndromic taas). mutations in the SLC2A10 gene.3 24 (Fa 1. patients can a also present with levido reticularis.include short stature. but only three genes have been identified: TGFBR2 in ta 2. hypertension and taas. stenosis and aneurysm formation in the major arteries owing to dis ruption of elastic fibers in the media caused by increased tGFβ1 activity in the arterial wall.

which seemed to invade the media. the precise mechanisms responsible for the aneurysmal vascular disorders remain largely unknown. ACTA2 mutations are thought to affect local adaptation of cellular and extracellular ele ments to mechanical stresses through dysfunction of the mechanotransduction pathways. 23. a hallmark of aneurysmal aortas. analysis of aneurysmal aortic tissue a shows a decreased number of vsmCs.24.139 Familial TAA2 vasa vasorum. 25 Focal areas of increased vsmCs that have no organized alignment. the ACTA2 gene encodes smooth muscle α2actin (one of six identified actin isoforms). subsequent analysis of three unrelated families with taa and patent ductus arteriosus identi fied missense point mutations in the MYH11 gene in two families (the remaining family had a TGFβR2 muta tion).27. 26 the presence of a concomitant patent ductus arteriosus in patients with MYH11 mutations probably reflects a reduced ability of vsmCs to proliferate. vsmCs isolated from two individuals heterozygous for ACTA2 mutations showed signifi cantly reduced smooth muscle α2actincontaining fila ments and aggregates of unpolymerized smooth muscle α 2actin in the analysis of 97 unrelated cytoplasm. as will be discussed later.137 notably. the mutations originally identi fied caused inframe deletions in MYH11 that seem to reduce the probability of adoption of a coiledcoil struc ture by βmHC. 137 Functionally. 137 the increase in vasa vasorum suggests possible inflamma tor y processes originating from the adventitial wall. making such mutations the most commonly identified cause of familial taas.138.26 vsmC disarray and focal areas of cell hyper plasia were also observed. Clinically. However. a major specific contrac tile protein in vsmCs. have also been observed.26. there was increased vascularity and marked fibromuscular dysplasia in the adventitial these changes translate into decreased aortic wall compli ance. 134 suggesting a widespread dysregulation of mechanotransduction pathways causing tissuespecific local responses. as well as increased vsmC proliferation in the adventitial vasa vasorum. families revealed ACTA2 mutations in 14 families (14%).98 increased expression of insulin growth factor i and angiotensin ii were also observed in aortas of MYH11 mutation carriers but their functional significance remains poorly defined. histological analysis of other taas has consistently shown the presence of inflam matory and immune infiltrates in the aortic wall that seem to originate from the vasa vasorum (the socalled ‘outsidein theory’).136 MYH11 encodes smooth muscle βmHC. 137 Histological analysis of affected aortas showed focal areas of vsmC loss. . as observed with ACTA2 mutations. MYH11 mutations MYH11 mutations have been linked to familial ta a and patent ductus arteriosus formation. evaluation of ACTA2 mutation carriers in 20 families has been associated with premature onset of coronary artery disease and ischemic strokes.48%) and does not increase with age.25 R EvI E W S arteriosus and nonthoracic aneurysms. fragmenta tion and loss of elastic fibers and accumulation of proteo glycans in the media. migrate and contract. resulting in failure of assembly of myosin thick filaments.135. unlike other forms of ta . and loss of elastic fibers and collagen. the penetrance of this mutation is low (0.

Patients with ta 2 present with aortic a aneurysms at varying ages and phenotypic manifestation shows reduced penetrance. which encodes tGFβr2. mutations in the ta 2 a locus result in increased tGFβ1 activity. Sporadic Taas sporadic taas occur in isolation and do not show any familial transmission. the precise mechanisms under lying the increased tGFβ signaling remain unknown. yet hetero zygous germ line mutations in the same gene result in the vascular phenotype and no apparent predisposition to cancer.83.140 in all cases.83 or because tGFβ might have a role a in cancer progression but not in tumor initiation. they encompass a range of causative etiologies. accompanied by matrix degradation and elastin fragmentation. but the precise cellular and molecu lar mechanisms remain poorly understood. However. thus reducing signal transduction. somatic mutations in tGFβr2 have been associated with an increased risk of cancer. similarly to observations in patients with loeys– Dietz syndrome. possibly because a wildtype receptor is present in addition to the mutated receptor in patients with ta 2. All rights reserved s . the ta 2 a mutation involves arg460 in the intracellular receptor domain. inflammatory (giant cell arteritis143). rheumatoid arthritis or reiter syndrome). the causative mutations are located in the ta 2 a locus on chromosome 3p2425.83. this obser vation is consistent with findings of increased tGFβ1 signaling in a transgenic mouse model of fibro blastspecific kinasedeficient tGFβr2.Familial ta 2 is one of the nonsyndromic a familial taas (table 1). the extracellular tGFβbinding domain remains structurally intact and presumably its ability to bind tGFβ1 is preserved.142 However. nat r e rev ews | cardiolog u i | 781 y volume 6 | DeCem Ber 2009 © 2009 Macmillan Publisher Limited. infectious (syphilis or tuberculosis) or traumatic conditions. as previously mentioned. ta 2 is an a autosomaldominant disorder with reduced penetrance and variable expression. interestingly. little is known about the precise pathophysiological mecha nisms involved in sporadic taas.141 mutations in the arg460 amino acid are thought to disrupt Fhelix Dhelix communications within the threedimensional struc ture of the receptor. most of these aneu rysms are characterized by inflammatory and immune cell infiltration in the aortic wall. autoimmune (takayasu arteritis. sporadic taas can originate from ‘degenerative’. several new approaches targeting molecular pathways have shown promising results. New therapeutic approaches on the basis of the present understanding of the patho genic mechanisms of taa formation.

151 in addition to the decrease in mmP2 and mmP9 activation.144 losartan treatment resulted in a significant reduction in aortic size and growth. 150 these results were corro borated by a separate study comparing doxycyclin with atenolol in the treatment of fibrillin 1deficient mice. no human studies have been performed but preliminary results from animal models are promising. a they suggest a potentially dif ferent pathophysiological role of tGFβ1 in degenerative taas.54 mm per r year to 0. randomized trial is currently underway comparing losartan to atenolol (a βblocker) in a larger cohort of patients. more collagen. 145. showed a decrease in elastic fiber fragmen tation and decreased expression of mm P2 and mm P9 in fibrillin 1deficient mice.148 a prospective. the authors demonstrated a decrease in tGFβ1 expres sion and activity in the doxycyclin group.151 to date. anti-inflammatory and antioxidative agents although the role of inflammatory and oxidative mecha nisms in the pathogenesis of taas remains unclear.146 as well as decreasing smad activation through tGFβ1independent pathways. a potent mediator of angiotensin iiinduced tGFβ1 activation via at1.46 mm per year.R EvI E W S a Bs r administration of tGFβ1neutralizing antibodies to fibrillin 1deficient mice reverses the damaging effects associated with tGFβ1 hyperactivity in the aortic wall.5 years) showed a significant reduction in the rate of progression of aortic wall dilatation following treat ment with a Bs. tGFβ1 –/– supplementation in ApoE mice was found to prevent aortic root dilatation in a single study. a lower expression of inflammatory cytokines and a reduction in mm P13 expression. we believe that valuable data from the abdominal aneurysm doxycyclin Doxycyclin is a nonspecific mm P inhibitor that has been used for the treatment of conditions associated with increased mm P activity. treated 7weekold fibrillin 1deficient mice with documented taas with the βadrenoceptor antagonist propranol or with losartan for a period of 6 months. given the cumulative evidence implicating . Xiong et al. treated mice did not develop taas and had normal mechanical properties of the ascending aorta.144 the a B losartan mediates a similar r effect. Habashi et al.144 the precise mechanisms explaining the role of losartan are still poorly understood although it is thought to reduce the expression of tsP1. highlighting its pleiotropic effects.152 these aortas had fewer t lymphocytes. TgF-β1 although most evidence points to a putative role of increased tGFβ1 activity in the pathogenesis of taas. as well as improved aortic wall architecture.152 although these findings are provocative. 149 tGFβ1 in ta formation. such as rheumatoid arthritis.147 a pilot study in 18 pediatric patients with marfan syndrome (median age 6. decreasing from 3. importantly.

100.154 other possible targets include mm P2 and mm P9 but their circulating serum levels have not yet yielded enough sensitivity and specificity to be clinically useful.com/nrcardio .nature. such studies could help identify highrisk. Future directions the past 10–15 years have witnessed an unprecedented rate of advance in the understanding of taa patho genesis. All rights reserved s www. Finally. For example. a tailored evaluation of a patient’s risk of aortic Biomarkers 782 | DECEMBER 2009 | voluME 6 © 2009 Macmillan Publisher Limited. high mm P activity) despite a normal aortic diameter. par ticularly sp oradi c forms of the disease. in addition to genetic and mechanis tic understanding of cellular and molecular mechanisms of taas. researchers using animal models of abdominal aneurysms have found a role for cyclophilin a or JnK inhibition in preventing aneurysm formation.158 these estimations take into account the individual properties of the aorta. including the level and location of mm P activity. three important areas—molecular imaging. have examined the pathophysiology of aortic valve disease and have demonstrated the feasibility of in vivo molecular imaging of the pathophysiological steps involved in valve calcification. as well as the tensile strength of the aorta (Figure 9). treatment with losartan. research is currently ongoing to identify circulating or genetic biomarkers of taas. a study has sug gested that serum tGFβ1 levels correlate with the aortic size in patients with marfan syndrome.154 more impor tantly. identification of biomarkers and computational model ing— might have major clinical implications by allowing individualized manageme nt of patients with taas.153 similar studies would allow a better understanding of the spatiotemporal sequence of events leading to ta formation and would also allow detection of a firstdegree relatives with ‘meta bolically active aortas’ (for example. these findings have changed our perception of the disease and paved the way for many more develop ments in the future.literature should be considered in the study of taas.101 these data are of particular interest and represent a promising avenue in the prevention or mitigation of the progression of aneurysms. in this regard. which can vary con siderably between patients whose disease shares a similar etiology. which could therefore be evaluated as a potential therapeutic target. mildly dilated aortas (40–50 mm).155–157 Molecular imaging aikawa et al. βadrenoceptor antago nists or a combination of both resulted in a significant decrease in the levels of circulating tGFβ1. computational imaging the rapid development of computational fluid dynamics and structural mechanics for the assessment of the aortic root allows creation of patientspecific models that esti mate stresses along the aortic root (wall shear stress and tens ile stress).

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