transforming-growth-factor-beta and Aortic-Aneurysm--Thoracic

Thoracic aortic aneurysms (TAAs) are permanent pathological dilatations of the thoracic aorta, which can lead to life-threatening complications, such as aortic dissection and rupture. TAAs frequently occur in a syndromic form in individuals with an underlying genetic predisposition, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Increasing evidence supports an important role for transforming growth factor-β (TGF-β) and the renin-angiotensin system (RAS) in TAA pathology. Eventually, most patients with syndromic TAAs require surgical intervention, as the ability of present medical treatment to attenuate aneurysm growth is limited. Therefore, more effective medical treatment options are urgently needed. Numerous clinical trials investigated the therapeutic potential of angiotensin receptor blockers (ARBs) and β-blockers in patients suffering from syndromic TAAs. This review highlights the contribution of TGF-β signaling, RAS, and impaired mechanosensing abilities of aortic VSMCs in TAA formation. Furthermore, it critically discusses the most recent clinical evidence regarding the possible therapeutic benefit of ARBs and β-blockers in syndromic TAA patients and provides future research perspectives and therapeutic implications.

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Animals; Aortic Aneurysm, Thoracic; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; MAP Kinase Signaling System; Mice; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Signal Transduction; Syndrome; Transforming Growth Factor beta

Thoracic aortic aneurysms that progress to acute aortic dissections are often fatal. Thoracic aneurysms have been managed with treatment with β-adrenergic blocking agents (β-blockers) and routine surveillance imaging, followed by surgical repair of the aneurysm when the risk of dissection exceeds the risk for repair. Thus, there is a window to initiate therapies to slow aortic enlargement and delay or ideally negate the need for surgical repair of the aneurysm to prevent a dissection. Mouse models of Marfan syndrome-a monogenic disorder predisposing to thoracic aortic disease-have been used extensively to identify such therapies. The initial finding that TGFβ (transformation growth factor-β) signaling was increased in the aortic media of a Marfan syndrome mouse model and that its inhibition via TGFβ neutralization or At1r (Ang II [angiotensin II] type I receptor) antagonism prevented aneurysm development was generally viewed as a groundbreaking discovery that could be translated into the first cure of thoracic aortic disease. However, several large randomized trials of pediatric and adult patients with Marfan syndrome have subsequently yielded no evidence that At1r antagonism by losartan slows aortic enlargement more effectively than conventional treatment with β-blockers. Subsequent studies in mouse models have begun to resolve the complex molecular pathophysiology underlying onset and progression of aortic disease and have emphasized the need to preserve TGFβ signaling to prevent aneurysm formation. This review describes critical experiments that have influenced the evolution of our understanding of thoracic aortic disease, in addition to discussing old controversies and identifying new therapeutic opportunities.

Topics: Acute Disease; Angiotensin II; Animals; Aortic Aneurysm, Thoracic; Aortic Dissection; Humans; Losartan; Mice; Signal Transduction; Transforming Growth Factor beta

Topics: Adaptor Proteins, Signal Transducing; Aged; Aged, 80 and over; Animals; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Aortitis; Cilostazol; Disease Models, Animal; Female; Genetic Predisposition to Disease; Humans; Macrophage Activation; Male; Mice; Risk Factors; Sex Factors; Transforming Growth Factor beta

Recent advances in DNA sequencing technology have identified several causative genes for hereditary thoracic aortic aneurysms and dissections (TAADs), including Marfan syndrome (MFS), Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome, and familial non-syndromic TAADs. Syndromic TAADs are typically caused by pathogenic variants in the transforming growth factor-β signal and extracellular matrix-related genes (e.g. FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2, and COL3A1). On the other hand, approximately 20% of the non-syndromic hereditary TAADs result from altered components of the contractile apparatus of vascular smooth muscle cells, which are encoded by ACTA2, MYH11, MYLK, and PRKG1 genes; however, the remaining 80% cannot be explained by previously reported candidate genes. Moreover, the relationship between the genotype and phenotype of TAADs has extensively been reported to investigate better methods for risk stratification and further personalized treatment strategies. With regard to MFS-causing FBN1, recent reports have shown significantly increased risk of aortic events in patients carrying a truncating variant or a variant exhibiting a haploinsufficient-type effect, typically comprising nonsense or small insertions/deletions resulting in out-of-frame effects, compared to those carrying a variant with dominant negative-type effect, typically comprising missense variants. Therefore, cardiologists are required to have sufficient knowledge regarding the genetics of hereditary TAADs for providing the best clinical management, with an appropriate genetic counseling. In the current review, we present current advances in the genetics of hereditary TAADs and discuss the benefits and limitations with respect to the use of this genetic understanding in clinical settings.

Topics: Actins; Aortic Aneurysm, Thoracic; Aortic Dissection; Calcium-Binding Proteins; Collagen Type III; Cyclic GMP-Dependent Protein Kinase Type I; Female; Fibrillin-1; Humans; Male; Muscle, Smooth, Vascular; Myosin Heavy Chains; Myosin-Light-Chain Kinase; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Transforming Growth Factor beta2

Thoracic aortic aneurysms (TAAs) are common, life-threatening diseases and are a major cause of mortality and morbidity. Over the past decade, genetic approaches have revealed that 1) activation of the transforming growth factor beta (TGF-β) signaling, 2) alterations in the contractile apparatus of vascular smooth muscle cells (SMCs), and 3) defects in the extracellular matrix (ECM) were responsible for development of TAAs. Most recently, a fourth mechanism has been proposed in that dysfunction of mechanosensing in the aortic wall in response to hemodynamic stress may be a key driver of TAAs. Interestingly, the elastin-contractile unit, which is an anatomical and functional unit connecting extracellular elastic laminae to the intracellular SMC contractile filaments, via cell surface receptors, has been shown to play a critical role in the mechanosensing of SMCs, and many genes identified in TAAs encode for proteins along this continuum. However, it is still debated whether these four pathways converge into a common pathway. Currently, an effective therapeutic strategy based on the underlying mechanism of each type of TAAs has not been established. In this review, we will update the present knowledge on the molecular mechanism of TAAs with a focus on the signaling pathways potentially involved in the initiation of TAAs. Finally, we will evaluate current therapeutic strategies for TAAs and propose new directions for future treatment of TAAs.

Topics: Animals; Aortic Aneurysm, Thoracic; Extracellular Matrix; Humans; Muscle, Smooth, Vascular; Signal Transduction; Transforming Growth Factor beta

Microfibril-associated glycoproteins 1 and 2 (MAGP-1, MAGP-2) are protein components of extracellular matrix microfibrils. These proteins interact with fibrillin, the core component of microfibrils, and impart unique biological properties that influence microfibril function in vertebrates. MAGPs bind active forms of TGFβ and BMPs and are capable of modulating Notch signaling. Mutations in MAGP-1 or MAGP-2 have been linked to thoracic aneurysms and metabolic disease in humans. MAGP-2 has also been shown to be an important biomarker in several human cancers. Mice lacking MAGP-1 or MAGP-2 have defects in multiple organ systems, which reflects the widespread distribution of microfibrils in vertebrate tissues. This review summarizes our current understanding of the function of the MAGPs and their relationship to human disease.

Topics: Animals; Aortic Aneurysm, Thoracic; Biomarkers; Bone Morphogenetic Proteins; Contractile Proteins; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Metabolic Diseases; Mice; Mutation; Neoplasms; Receptors, Notch; RNA Splicing Factors; Signal Transduction; Transforming Growth Factor beta

Aortic aneurysms are morbid conditions that can lead to rupture or dissection and are categorized as thoracic (TAA) or abdominal aortic aneurysms (AAA) depending on their location. While AAA shares overlapping risk factors with atherosclerotic cardiovascular disease, TAA exhibits strong heritability. Human genetic studies in the past two decades have successfully identified numerous genes involved in both familial and sporadic forms of aortic aneurysm. In this review we will discuss the genetic basis of aortic aneurysm, focusing on the extracellular matrix and how insights from these studies have informed our understanding of human biology and disease pathogenesis.

Topics: Animals; Aortic Aneurysm; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Extracellular Matrix; Genetic Predisposition to Disease; Humans; Mutation; Signal Transduction; Transforming Growth Factor beta

Transforming growth factor-β (TGF)-β signaling plays a crucial role in the development and maintenance of various organs, including the vasculature. Accordingly, the mutations in TGF-β signaling pathway-related genes cause heritable disorders of the connective tissue, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS), and these syndromes may affect skeletal, ocular, pulmonary, and cardiovascular systems. Aortic root aneurysms are common problems that can result in aortic dissection or rupture, which is the leading cause of sudden death in the natural history of MFS and LDS, and recent improvements in surgical treatment have improved life expectancy. However, there is currently no genotype-specific medical treatment. Accumulating evidence suggest that not only structural weakness of connective tissue but also increased TGF-β signaling contributes to the complicated pathogenesis of aortic aneurysm formation, but a comprehensive understanding of governing molecular mechanisms remains lacking. Inhibition of angiotensin II receptor signaling and endothelial dysfunction have gained attention as a possible MFS treatment strategy, but interactions with TGF-β signaling remain elusive. Heterozygous loss-of-function mutations in TGF-β receptors 1 and 2 (

Topics: Angiotensin II; Animals; Aortic Aneurysm, Thoracic; Fibrillin-1; Humans; Loeys-Dietz Syndrome; Signal Transduction; Transforming Growth Factor beta

Thoracic aortic diseases, including aneurysms and dissections of the thoracic aorta, are a major cause of morbidity and mortality. Risk factors for thoracic aortic disease include increased hemodynamic forces on the ascending aorta, typically due to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease either disrupt smooth muscle cell (SMC) contraction or adherence to an impaired extracellular matrix, or decrease canonical transforming growth factor beta (TGF-β) signaling. Paradoxically, TGF-β hyperactivity has been postulated to be the primary driver for the disease. More recently, it has been proposed that the response of aortic SMCs to the hemodynamic load on a structurally defective aorta is the primary driver of thoracic aortic disease, and that TGF-β overactivity in diseased aortas is a secondary, unproductive response to restore tissue function. The engineering of mouse models of inherited aortopathies has identified potential therapeutic agents to prevent thoracic aortic disease.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Aortic Aneurysm, Thoracic; Aortic Dissection; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Losartan; Marfan Syndrome; Mechanoreceptors; Mice; Muscle, Smooth, Vascular; Signal Transduction; Transforming Growth Factor beta

Aneurysms are characterized by structural deterioration of the vascular wall leading to progressive dilatation and, potentially, rupture of the aorta. While aortic aneurysms often remain clinically silent, the morbidity and mortality associated with aneurysm expansion and rupture are considerable. Over 13,000 deaths annually in the United States are attributable to aortic aneurysm rupture with less than 1 in 3 persons with aortic aneurysm rupture surviving to surgical intervention. Environmental and epidemiologic risk factors including smoking, male gender, hypertension, older age, dyslipidemia, atherosclerosis, and family history are highly associated with abdominal aortic aneurysms, while heritable genetic mutations are commonly associated with aneurysms of the thoracic aorta. Similar to other forms of cardiovascular disease, family history, genetic variation, and heritable mutations modify the risk of aortic aneurysm formation and provide mechanistic insight into the pathogenesis of human aortic aneurysms. This review will examine the relationship between heritable genetic and epigenetic influences on thoracic and abdominal aortic aneurysm formation and rupture.

Topics: Aged; Aging; Aorta, Thoracic; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Aortic Rupture; Disease Progression; Epigenesis, Genetic; Extracellular Matrix; Female; Genetic Predisposition to Disease; Humans; Inflammation; Lipids; Male; Marfan Syndrome; Models, Genetic; Muscle, Smooth; Mutation; Polymorphism, Single Nucleotide; Risk Factors; Sequence Analysis, DNA; Smoking; Transforming Growth Factor beta

Recent progress in the study of hereditary large vessel diseases such as Marfan syndrome (MFS) have not only identified responsible genes but also provided better understanding of the pathophysiology and revealed possible new therapeutic targets. Genes identified for these diseases include FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3, SKI, EFEMP2, COL3A1, FLNA, ACTA2, MYH11, MYLK and SLC2A10, as well as others. Their dysfunction disrupts the function of transforming growth factor-β (TGF-β) signaling pathways, as well as that of the extracellular matrix and smooth muscle contractile apparatus, resulting in progression of structural damage to large vessels, including aortic aneurysms and dissections. Notably, it has been shown that the TGF-β signaling pathway has a key role in the pathogenesis of MFS and related disorders, which may be important for development of strategies for medical and surgical treatment of thoracic aortic aneurysms and dissections.

Topics: Aortic Aneurysm, Thoracic; Aortic Dissection; Ehlers-Danlos Syndrome; Fibrillin-1; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Mutation; Signal Transduction; Transforming Growth Factor beta

Cardiovascular abnormalities are the major cause of morbidity and mortality in Marfan syndrome (MFS) and a few clinically related diseases that share, with MFS, the pathogenic contribution of dysregulated transforming growth factor β (TGFβ) signaling. They include Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome, aneurysm-osteoarthritis syndrome and syndromic thoracic aortic aneurysms. Unlike the causal association of MFS with mutations in an extracellular matrix protein (ECM), the aforementioned conditions are due to defects in components of the TGFβ pathway. While TGFβ antagonism is being considered as a potential new therapy for these heritable syndromes, several points still need to be clarified in relevant animal models before this strategy could be safely applied to patients. Among others, unresolved issues include whether elevated TGFβ signaling is responsible for all MFS manifestations and is the common trigger of disease in MFS and related conditions. The scope of our review is to highlight the clinical and experimental findings that have forged our understanding of the natural history and molecular pathogenesis of cardiovascular manifestations in this group of syndromic conditions.

Topics: Animals; Aortic Aneurysm, Thoracic; Arachnodactyly; Cardiovascular Abnormalities; Craniosynostoses; Fibrillin-1; Fibrillins; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Mice; Microfilament Proteins; Signal Transduction; Transforming Growth Factor beta

Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that cosegregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic root dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. Given the evidence of increased transforming growth factor-beta (TGF-β) signaling in MFS and LDS, this signaling pathway may represent the common link in this relationship. To further explore this hypothetical link, this chapter will review the TGF-β signaling pathway, heritable connective tissue syndromes related to TGF-β receptor (TGFBR) mutations, and discuss the pathogenic contribution of TGF-β to these syndromes with a primary focus on the cardiovascular system.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Antibodies, Neutralizing; Aortic Aneurysm, Thoracic; Aortic Valve; Bicuspid Aortic Valve Disease; Gene Expression Regulation; Heart Defects, Congenital; Heart Valve Diseases; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Mutation; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

A lot of new data have been obtained in familial thoracic aortic aneurysms, including description of new entities and better understanding of pathophysiology. The aim of this review is to put them in perspective.. The new data have been collected, put together, and allowed a new classification scheme to be proposed by the Montalcino Aortic Consortium on the basis of the role of proteins coded by the culprit gene (either protein of the extracellular matrix or protein of the transforming growth factor-beta pathway, or protein of the contractile apparatus of the smooth muscle cell). These groups of diseases include aortic aneurysm, but the extent of extra-aortic vascular risk and the presence of extra-aortic (skeletal, ophthalmologic, neurological, or immunological) features vary according to the gene involved. This understanding also sheds light on the therapeutic benefits that can be foreseen for new molecules, or old molecules used in a newer way.. Classification of familial forms of thoracic aortic aneurysm should allow a better understanding of these diseases and therefore standardization of initial evaluation of the patients (vascular evaluation limited or not to the aorta, and extravascular evaluation, including or not skeleton, eyes, neurology, digestive tract, and immunological diseases) and individualization of therapy (adapted to both the genotype and the phenotype).

Topics: Aortic Aneurysm, Thoracic; DNA; Genetic Predisposition to Disease; Genotype; Humans; Muscle, Smooth, Vascular; Mutation; Transforming Growth Factor beta

Aortic aneurysm, including both abdominal aortic aneurysm and thoracic aortic aneurysm, is the cause of death of 1% to 2% of the Western population. This review focuses only on thoracic aortic aneurysms and dissections. During the past decade, the genetic contribution to the pathogenesis of thoracic aortic aneurysms and dissections has revealed perturbed extracellular matrix signaling cascade interactions and deficient intracellular components of the smooth muscle contractile apparatus as the key mechanisms. Based on the study of different Marfan mouse models and the discovery of several novel thoracic aortic aneurysm genes, the involvement of the transforming growth factor-β signaling pathway has opened unexpected new avenues. Overall, these discoveries have 3 important consequences. First, the pathogenesis of thoracic aortic aneurysms and dissections is better understood, although some controversy still exists. Second, the management strategies for the medical and surgical treatment of thoracic aortic aneurysms and dissections are becoming increasingly gene-tailored. Third, the pathogenetic insights have delivered new treatment options that are currently being investigated in large clinical trials.

Topics: Animals; Aortic Aneurysm, Thoracic; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Transforming Growth Factor beta; Vasoconstriction

Thoracic aortic aneurysm and dissection in young and middle aged patients is increasingly recognised as due to genetic aortopathy. Mutations in multiple genes affecting proteins in the extracellular matrix, microfibrillar structure, the endothelium and cell signalling pathways have been associated with thoracic aortic disease. The TGFß signalling pathway appears to play a key role in mediating abnormal aortic growth and aneurysm formation. A challenge remains in understanding how the many different gene mutations can result in deranged TGFß signalling. This review examines the functional relationships between key structural and signalling proteins, with reference to the need for maintenance of homeostasis in mechanotransduction within the aortic wall. A mechanism, through which perturbations in mechanotransduction, arising from different gene mutations, results in altered TGFß signalling is described.

Topics: Animals; Aortic Aneurysm, Thoracic; Aortic Dissection; Humans; Mechanotransduction, Cellular; Mutation; Transforming Growth Factor beta

Heritable connective tissue diseases comprise a heterogeneous group of multisystemic disorders that are characterized by significant morbidity and mortality. These disorders do not merely result from defects in the amount or structure of one of the components of the extracellular matrix, as the extracellular matrix also serves other functions, including sequestration of cytokines, such as transforming growth factor beta (TGFβ). Indeed, disturbed TGFβ signaling was demonstrated in several heritable connective tissue diseases, including syndromic forms such as Marfan or Loeys-Dietz syndrome and non-syndromic presentations of thoracic aortic aneurysm/dissection. Because of these findings, new therapeutic targets have been unveiled, leading to the initiation of large clinical trials with angiotensin II type 1 receptor antagonists that also have an inhibiting effect on TGFβ signaling. Here, we present an overview of the clinical characteristics, the molecular findings, and the therapeutic strategies for the currently known syndromic and non-syndromic forms of thoracic aortic aneurysm/dissection.

Topics: Angiotensin II Type 1 Receptor Blockers; Aortic Aneurysm, Thoracic; Aortic Dissection; Humans; Transforming Growth Factor beta

Four distinguishing histopathological characteristics of thoracic aortic aneurysms and dissections (TAADs) are the fragmentation or degradation of elastic fibers, loss of smooth muscle, pooling of glycosaminoglycans, and remodeling of fibrillar collagens. Of these, pooling of glycosaminoglycans appears to be unique to these lesions.. This review acknowledges the importance of dysregulated transforming growth factor-β (TGF-β) in TAADs and offers a complementary hypothesis that increased TGF-β could contribute to the accumulation of glycosaminoglycans in the media of the proximal thoracic aorta. Regardless, observed pools of glycosaminoglycans could decrease tensile strength, cause stress concentrations, and increase intralamellar swelling pressure, all of which could initiate local delaminations that could subsequently propagate as dissections and result in a false lumen or rupture.. There is a pressing need to investigate potential mechanical as well as biological consequences of accumulated glycosaminoglycans in TAADs and to elucidate responsible signaling pathways, with particular attention to synthetic cells of nonmesodermal lineage. Such research could provide insight into the mechanisms of dissection and the seemingly paradoxical role of the over-expression of a cytokine that is typically associated with fibrosis but is implicated in a degenerative disease of the aorta that can result in a catastrophic mechanical failure.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Aortic Rupture; Biomechanical Phenomena; Glycosaminoglycans; Humans; Signal Transduction; Tensile Strength; Transforming Growth Factor beta

Although historically Marfan syndrome (MFS) has always been considered as a condition caused by the deficiency of a structural extracellular matrix protein, fibrillin-1, the study of Marfan mouse models and Marfan-related conditions has shifted our current understanding to a pathogenic model that involves dysregulation of the cytokine-transforming growth factor beta (TGF-β) signaling.. In this review, we focus on the impact of the revised MFS clinical diagnostic criteria. We discuss lessons that have been learned from molecular findings in relevant Marfan-related conditions, such as sporadic thoracic aortic aneurysm/dissection, stiff skin syndrome, acromelic dysplasias and Loeys-Dietz syndrome. We explore the latest insights into the role of the alternative TGF-β signaling pathways in MFS pathogenesis. Finally, we give an update on the current and future treatment strategies.. The recent insights into the pathogenesis of MFS and related disorders have offered a prime example of translational medicine with immediate bridge between molecular findings and therapeutic options.

Topics: Acromegaly; Adolescent; Aortic Aneurysm, Thoracic; Child; Child, Preschool; Female; Fibrillin-1; Fibrillins; Humans; Loeys-Dietz Syndrome; Male; Marfan Syndrome; Microfilament Proteins; Mutation; Signal Transduction; Transforming Growth Factor beta

Marfan syndrome is a systemic connective tissue disorder that is inherited in an autosomal-dominant pattern with variable penetrance. Although there are many clinical manifestations of this disease, the most life threatening are cardiovascular complications, including mitral valve prolapse and aortic root aneurysm. When the primary defect was discovered in the fibrillin-1 gene, it was hypothesized that mutations in fibrillin-1 resulted in a weakened and disordered elastic architecture. However, recent evidence has suggested that the Marfan syndrome is caused by more than just a disordered microfibril matrix. Interest was stimulated when it was discovered that fibrillin-1 mutations enhanced the release of sequestered latent transforming growth factor-beta, a well-described mediator of vascular remodeling. This article focuses on the pathophysiology of aortopathy in the Marfan syndrome and related diseases, with special emphasis on the role of transforming growth factor-beta in mediating the pathogenesis of this disease.

Topics: Aortic Aneurysm, Thoracic; Aortic Dissection; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Microfilament Proteins; Mitral Valve Prolapse; Mutation; Risk Factors; Signal Transduction; Transforming Growth Factor beta

Thoracic aortic aneurysms (TAAs) are potentially devastating, and due to their asymptomatic behavior, pose a serious health risk characterized by the lack of medical treatment options and high rates of surgical morbidity and mortality. Independent of the inciting stimuli (biochemical/mechanical), TAA development proceeds by a multifactorial process influenced by both cellular and extracellular mechanisms, resulting in alterations of the structure and composition of the vascular extracellular matrix (ECM). While the role of enhanced ECM proteolysis in TAA formation remains undisputed, little attention has been focused on the upstream signaling events that drive the remodeling process. Recent evidence highlighting the dysregulation of transforming growth factor-beta (TGF-beta) signaling in ascending TAAs from Marfan syndrome patients has stimulated an interest in this intracellular signaling pathway. However, paradoxical discoveries have implicated both enhanced TGF-beta signaling and loss of function TGF-beta receptor mutations, in aneurysm formation; obfuscating a clear functional role for TGF-beta in aneurysm development. In an effort to elucidate this subject, TGF-beta signaling and its role in vascular remodeling and pathology will be reviewed, with the aim of identifying potential mechanisms of how TGF-beta signaling may contribute to the formation and progression of TAA.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Disease Progression; Ehlers-Danlos Syndrome; Extracellular Matrix; Genetic Predisposition to Disease; Humans; Marfan Syndrome; Mutation; Peptide Hydrolases; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta

Aortic aneurysms are an important cause of mortality in the western world. Monogenic disorders such as the Marfan syndrome (MFS) are good genetic models for the pathogenesis of aortic aneurysm. In the MFS, progressive dilatation of the aortic root leads to aortic aneurysm and dissection, often associated with precocious death. Early pathogenetic models for MFS focused upon structural weakness of the tissues imposed by microfibrillar deficiency. However, recent studies of transgenic mouse models have challenged this model and demonstrated a central role for the upregulation of the TGFbeta signaling pathway. The discovery of a new aortic aneurysm syndrome, the Loeys-Dietz syndrome (LDS), confirmed the importance of the cytokine TGFbeta in aneurysm pathogenesis. The main distinguishing features between LDS and MFS include the presence of hypertelorism, cleft palate/bifid uvula and arterial tortuosity. LDS is caused by mutations in the genes encoding the receptors for TGFbeta (TGFBR1/2). This insight helped to elucidate the pathogenesis of another rare autosomal recessive connective tissue disorder, arterial tortuosity syndrome. This disease is caused by mutations in the SLC2A10 gene, coding for GLUT10, a member of the glucose transporter family. In analogy to LDS, we demonstrated an upregulation of TGFbeta in ATS. Finally, all these insights have also lead to new therapeutic insights. In transgenic mouse models it was shown that losartan, an angiotensin II type 1 receptor with known inhibiting effects on TGFbeta, rescues the aortic phenotype. If these promising results are confirmed in human trials, losartan might have beneficial effects in the treatment of more common nonhereditary aortic aneurysms.

Topics: Abnormalities, Multiple; Animals; Animals, Genetically Modified; Aortic Aneurysm; Aortic Aneurysm, Thoracic; Disease Models, Animal; Humans; Marfan Syndrome; Mice; Models, Genetic; Transforming Growth Factor beta; Up-Regulation

Marfan syndrome is a systemic connective tissue disorder caused by mutations in the fibrillin-1 gene. It was originally believed that Marfan syndrome results exclusively from the production of abnormal fibrillin-1 that leads to structurally weaker connective tissue when incorporated into the extracellular matrix. This effect seemed to explain many of the clinical features of Marfan syndrome, including aortic root dilatation and acute aortic dissection, which represent the main causes of morbidity and mortality in Marfan syndrome.. Recent molecular studies, most based on genetically defined mouse models of Marfan syndrome, have challenged this paradigm. These studies established the critical contribution of fibrillin-1 haploinsufficiency and dysregulated transforming growth factor-beta signaling to disease progression.. It seems that many manifestations of Marfan syndrome are less related to a primary structural deficiency of the tissues than to altered morphogenetic and homeostatic programs that are induced by altered transforming growth factor-beta signaling. Most important, transforming growth factor-beta antagonism, through transforming growth factor-beta neutralizing antibodies or losartan (an angiotensin II type 1 receptor antagonist), has been shown to prevent and possibly reverse aortic root dilatation, mitral valve prolapse, lung disease, and skeletal muscle dysfunction in a mouse model of Marfan syndrome.. There are indicators that losartan, a drug widely used to treat arterial hypertension in humans, offers the first potential for primary prevention of clinical manifestations in Marfan syndrome.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Aortic Aneurysm, Thoracic; Cohort Studies; Disease Models, Animal; Follow-Up Studies; Genetic Markers; Humans; Losartan; Marfan Syndrome; Mice; Microfilament Proteins; Risk Assessment; Survival Rate; Transforming Growth Factor beta; Treatment Outcome

In contrast with adults, thoracic aortic aneurysms in children are usually associated with connective tissue defect syndromes. As such, there are phenotypic clues to identify patients at risk. Marfan syndrome, Loeys-Dietz syndrome, and bicuspid aortic valve syndrome account for the majority of these aneurysms. Indications for surgery as well as surgical options differ according to diagnosis and are reviewed herein.

Topics: Aortic Aneurysm, Thoracic; Aortic Valve; Blood Vessel Prosthesis Implantation; Child; Ehlers-Danlos Syndrome; Humans; Marfan Syndrome; Mutation; Phenotype; Syndrome; Transforming Growth Factor beta

Marfan syndrome (MFS, OMIM #154700) is a hereditary connective tissue disorder, clinically presenting with cardinal features of skeletal, ocular, and cardiovascular systems. In classical MFS, changes in connective tissue integrity can be explained by defects in fibrillin-1, a major component of extracellular microfibrils. However, some of the clinical manifestations of MFS cannot be explained by mechanical properties alone. Recent studies manipulating mouse Fbn1 have provided new insights into the molecular pathogenesis of MFS. Dysregulation of transforming growth factor beta (TGFbeta) signaling in lung, mitral valve and aortic tissues has been implicated in mouse models of MFS. TGFBR2 and TGFBR1 mutations were identified in a subset of patients with MFS (MFS2, OMIM #154705) and other MFS-related disorders, including Loeys-Dietz syndrome (LDS, #OMIM 609192) and familial thoracic aortic aneurysms and dissections (TAAD2, #OMIM 608987). These data indicate that genetic heterogeneity exists in MFS and its related conditions and that regulation of TGFbeta signaling plays a significant role in these disorders.

Topics: Abnormalities, Multiple; Animals; Aortic Aneurysm, Thoracic; Craniosynostoses; Fibrillin-1; Fibrillins; Germ-Line Mutation; Humans; Marfan Syndrome; Mice; Microfilament Proteins; Models, Genetic; Transforming Growth Factor beta

When aortic cells are under stress, such as increased hemodynamic pressure, they adapt to the environment by modifying their functions, allowing the aorta to maintain its strength. To understand the regulation of this adaptive response, we examined transcriptomic and epigenomic programs in aortic smooth muscle cells (SMCs) during the adaptive response to AngII (angiotensin II) infusion and determined its importance in protecting against aortic aneurysm and dissection (AAD).. We performed single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) analyses in a mouse model of sporadic AAD induced by AngII infusion. We also examined the direct effects of YAP (yes-associated protein) on the SMC adaptive response in vitro. The role of YAP in AAD development was further evaluated in AngII-infused mice with SMC-specific. In wild-type mice, AngII infusion increased medial thickness in the thoracic aorta. Single-cell RNA sequencing analysis revealed an adaptive response in thoracic SMCs characterized by upregulated genes with roles in wound healing, elastin and collagen production, proliferation, migration, cytoskeleton organization, cell-matrix focal adhesion, and PI3K-PKB/Akt (phosphoinositide-3-kinase-protein kinase B/Akt) and TGF-β (transforming growth factor beta) signaling. ScATAC-seq analysis showed increased chromatin accessibility at regulatory regions of adaptive genes and revealed the mechanical sensor YAP/transcriptional enhanced associate domains as a top candidate transcription complex driving the expression of these genes (eg,. Aortic stress triggers the systemic epigenetic induction of an adaptive response (eg, wound healing, proliferation, matrix organization) in thoracic aortic SMCs that depends on functional biomechanical signal transduction (eg, YAP signaling). Our study highlights the importance of the adaptive response in maintaining aortic homeostasis and preventing AAD in mice.

Topics: Aneurysm; Animals; Aorta; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Cells, Cultured; Chromatin; Collagen; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Smooth Muscle; Proto-Oncogene Proteins c-akt; Transforming Growth Factor beta

Although abnormal TGFβ signaling is observed in several heritable forms of thoracic aortic aneurysms and dissections including Marfan syndrome, its precise role in aortic disease progression is still disputed. Using a mouse genetic approach and quantitative isobaric labeling proteomics, we sought to elucidate the role of TGFβ signaling in three Fbn1 mutant mouse models representing a range of aortic disease from microdissection (without aneurysm) to aneurysm (without rupture) to aneurysm and rupture. Results indicated that reduced TGFβ signaling and increased mast cell proteases were associated with microdissection. In contrast, increased abundance of extracellular matrix proteins, which could be reporters for positive TGFβ signaling, were associated with aneurysm. Marked reductions in collagens and fibrillins, and increased TGFβ signaling, were associated with aortic rupture. Our data indicate that TGFβ signaling performs context-dependent roles in the pathogenesis of thoracic aortic disease.

Topics: Aortic Aneurysm, Thoracic; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Transforming Growth Factor beta

Aortic root aneurysm is a common cause of morbidity and mortality in Loeys-Dietz and Marfan syndromes, where perturbations in transforming growth factor beta (TGFβ) signaling play a causal or contributory role, respectively. Despite the advantages of cross-species disease modeling, animal models of aortic root aneurysm are largely restricted to genetically engineered mice. Here, we report that zebrafish devoid of the genes encoding latent-transforming growth factor beta-binding protein 1 and 3 (ltbp1 and ltbp3, respectively) develop rapid and severe aneurysm of the outflow tract (OFT), the aortic root equivalent. Similar to syndromic aneurysm tissue, the distended OFTs display evidence for paradoxical hyperactivated TGFβ signaling. RNA-sequencing revealed significant overlap between the molecular signatures of disease tissue from mutant zebrafish and a mouse model of Marfan syndrome. Moreover, chemical inhibition of TGFβ signaling in wild-type animals phenocopied mutants but chemical activation did not, demonstrating that TGFβ signaling is protective against aneurysm. Human relevance is supported by recent studies implicating genetic lesions in LTBP3 and, potentially, LTBP1 as heritable causes of aortic root aneurysm. Ultimately, our data demonstrate that zebrafish can now be leveraged to interrogate thoracic aneurysmal disease and identify novel lead compounds through small-molecule suppressor screens. This article has an associated First Person interview with the first author of the paper.

Topics: Animals; Aortic Aneurysm, Thoracic; Dilatation; Humans; Larva; Latent TGF-beta Binding Proteins; Marfan Syndrome; Mice; Transforming Growth Factor beta; Zebrafish; Zebrafish Proteins

Mural cells in ascending aortic aneurysms undergo phenotypic changes that promote extracellular matrix destruction and structural weakening. To explore this biology, we analyzed the transcriptional features of thoracic aortic tissue.. Single-nuclear RNA sequencing was performed on 13 samples from human donors, 6 with thoracic aortic aneurysm, and 7 without aneurysm. Individual transcriptomes were then clustered based on transcriptional profiles. Clusters were used for between-disease differential gene expression analyses, subcluster analysis, and analyzed for intersection with genetic aortic trait data.. We sequenced 71 689 nuclei from human thoracic aortas and identified 14 clusters, aligning with 11 cell types, predominantly vascular smooth muscle cells (VSMCs) consistent with aortic histology. With unbiased methodology, we found 7 vascular smooth muscle cell and 6 fibroblast subclusters. Differentially expressed genes analysis revealed a vascular smooth muscle cell group accounting for the majority of differential gene expression. Fibroblast populations in aneurysm exhibit distinct behavior with almost complete disappearance of quiescent fibroblasts. Differentially expressed genes were used to prioritize genes at aortic diameter and distensibility genome-wide association study loci highlighting the genes. Using nuclear RNA sequencing, we describe the cellular diversity of healthy and aneurysmal human ascending aorta. Sporadic aortic aneurysm is characterized by differential gene expression within known cellular classes rather than by the appearance of novel cellular forms. Single-nuclear RNA sequencing of aortic tissue can be used to prioritize genes at aortic trait loci.

Topics: Actinin; Aorta; Aortic Aneurysm; Aortic Aneurysm, Thoracic; Genome-Wide Association Study; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; RNA, Nuclear; Sequence Analysis, RNA; Transforming Growth Factor beta

Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that segregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. With overwhelming evidence of the involvement of aberrant Transforming Growth Factor-beta (TGF-β) signaling in MFS and LDS, this signaling pathway may represent the common link in the relationship between connective tissue disorders and their associated cardiovascular complications. To further explore this hypothetical link, this chapter will review the TGF-β signaling pathway, the heritable connective tissue syndromes related to aberrant TGF-β signaling, and will discuss the pathogenic contribution of TGF-β to these syndromes with a primary focus on the cardiovascular system.

Topics: Aortic Aneurysm, Thoracic; Cardiovascular System; Connective Tissue; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factors

The molecular and cellular processes leading to aortic aneurysm development in Marfan syndrome (MFS) remain poorly understood. In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic aneurysm tissues from patients with MFS (

Topics: Adult; Aortic Aneurysm, Thoracic; Case-Control Studies; Cell Differentiation; Female; Gene Expression Regulation; Humans; Male; Marfan Syndrome; Receptors, Transforming Growth Factor beta; Signal Transduction; Single-Cell Analysis; Transforming Growth Factor beta; Young Adult

Topics: Adult; Animals; Aortic Aneurysm, Thoracic; beta Karyopherins; Child; Child, Preschool; Female; Humans; Loss of Function Mutation; Loss of Heterozygosity; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pedigree; Phenotype; Signal Transduction; Syndrome; Transforming Growth Factor beta; Young Adult

Stanford type A aortic dissection (TAAD) is one of the most dangerous cardiovascular diseases. MicroRNAs (miRNAs) have been considered as potential therapeutic targets for TAAD. In this present study, we aimed to investigate the functional role and regulatory mechanism of miR-26b in TAAD development.. MiR-26b mRNA expression was detected by real-time polymerase chain reaction (RT-PCR) and protein levels were measured by Western blot. Verifying the direct target of miR-26b was used by dual luciferase assay, RT-PCR, and Western blot. Cell Counting Kit-8 (CCK-8) and TUNEL staining assays were applied for detecting rat aortic vascular smooth muscle cells (VSMCs) viability and apoptosis, respectively.. We found that miR-26b was under-expressed in TAAD patients and closely associated with the poor prognosis of TAAD patients. Re-expression of miR-26b facilitated while knockdown of miR-26b inhibited VSMC proliferation. However, miR-26b showed the opposite effect on cell apoptosis. More importantly, high-mobility group AT-hook 2 (HMGA2) was verified as the direct target of miR-26b. Furthermore, transforming growth factor beta (TGF-β)/Smad3 signaling pathway was involved in the development of TAAD modulated by miR-26b.. miR-26b impeded TAAD development by regulating HMGA2 and TGF-β/Smad3 signaling pathway, which provided a potential biomarker for TAAD treatment.

Topics: Adult; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Apoptosis; Cells, Cultured; Female; Gene Expression Regulation; HMGA2 Protein; Humans; Male; MicroRNAs; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Rats; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

SMAD3 pathogenic variants are associated with the development of thoracic aortic aneurysms. We sought to determine the role of SMAD3 in lineage-specific vascular smooth muscle cells (VSMCs) differentiation and function. Approach and Results:. SMAD3-dependent TGF-β signaling was essential for the differentiation of cardiovascular progenitor cell-VSMCs but not for the differentiation of neural crest stem cell-VSMCs. The lineage-specific TGF-β responses in human VSMCs may potentially contribute to the development of aortic root aneurysms in patients with

Topics: Aortic Aneurysm, Thoracic; Cell Differentiation; Cell Lineage; Cells, Cultured; Elastin; Extracellular Matrix; Frameshift Mutation; Gene Expression Regulation; Humans; Induced Pluripotent Stem Cells; MicroRNAs; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta; Vascular Remodeling; Vasoconstriction

Topics: Androgens; Animals; Aortic Aneurysm, Thoracic; Fibrillin-1; Male; Marfan Syndrome; Mice; Transforming Growth Factor beta

Mutations in extracellular matrix and smooth muscle cell contractile proteins predispose to thoracic aortic aneurysms in Marfan syndrome (MFS) and related disorders. These genetic alterations lead to a compromised extracellular matrix-smooth muscle cell contractile unit. The abnormal aortic tissue responds with defective mechanosensing under hemodynamic stress. Aberrant mechanosensing is associated with transforming growth factor-beta (TGF-β) hyperactivity, enhanced angiotensin-II (Ang-II) signaling, and perturbation of other cellular signaling pathways. The downstream consequences include enhanced proteolytic activity, expression of inflammatory cytokines and chemokines, infiltration of inflammatory cells in the aortic wall, vascular smooth muscle cell apoptosis, and medial degeneration. Mouse models highlight aortic inflammation as a contributing factor in the development of aortic aneurysms. Anti-inflammatory drugs and antioxidants can reduce aortic oxidative stress that prevents aggravation of aortic disease in MFS mice. Targeting TGF-β and Ang-II downstream signaling pathways such as ERK1/2, mTOR, PI3/Akt, P38/MAPK, and Rho kinase signaling attenuates disease pathogenesis. Aortic extracellular matrix degradation and medial degeneration were reduced upon inhibition of inflammatory cytokines and matrix metalloproteinases, but the latter lack specificity. Treating inflammation associated with aortic aneurysms in MFS and related disorders could prove to be beneficial in limiting disease pathogenesis.

Topics: Animals; Aortic Aneurysm, Thoracic; Inflammation; Marfan Syndrome; Mice; Transforming Growth Factor beta

Thoracic aortic aneurysm and dissection (TAAD) are severe vascular conditions. Dysfunctional transforming growth factor-β (TGF-β) signaling in vascular smooth muscle cells and elevated angiotensin II (AngII) levels are implicated in the development of TAAD. In this study, we investigated whether these 2 factors lead to TAAD in a mouse model and explored the possibility of using microRNA-21 (. TAAD was developed in. Our study demonstrated that

Topics: Angiotensin II; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Aortic Rupture; Cells, Cultured; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Extracellular Signal-Regulated MAP Kinases; Genetic Predisposition to Disease; JNK Mitogen-Activated Protein Kinases; Male; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Phosphorylation; Signal Transduction; Smad3 Protein; Smad7 Protein; Transforming Growth Factor beta

Thoracic aortic aneurysm (TAA) has been associated with mutations affecting members of the TGF-β signaling pathway, or components and regulators of the vascular smooth muscle cell (VSMC) actomyosin cytoskeleton. Although both clinical groups present similar phenotypes, the existence of potential common mechanisms of pathogenesis remain obscure. Here we show that mutations affecting TGF-β signaling and VSMC cytoskeleton both lead to the formation of a ternary complex comprising the histone deacetylase HDAC9, the chromatin-remodeling enzyme BRG1, and the long noncoding RNA MALAT1. The HDAC9-MALAT1-BRG1 complex binds chromatin and represses contractile protein gene expression in association with gain of histone H3-lysine 27 trimethylation modifications. Disruption of Malat1 or Hdac9 restores contractile protein expression, improves aortic mural architecture, and inhibits experimental aneurysm growth. Thus, we highlight a shared epigenetic pathway responsible for VSMC dysfunction in both forms of TAA, with potential therapeutic implication for other known HDAC9-associated vascular diseases.

Topics: Actomyosin; Animals; Aorta; Aortic Aneurysm, Thoracic; Cell Line; Cell Nucleus; Chromatin; Disease Models, Animal; DNA Helicases; DNA Methylation; Female; Fluorescent Antibody Technique; Histone Deacetylases; Histones; Humans; Male; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Nuclear Proteins; Phenotype; Primary Cell Culture; Repressor Proteins; RNA Interference; RNA, Long Noncoding; RNA, Small Interfering; Signal Transduction; Transcription Factors; Transforming Growth Factor beta

Thoracic aortic aneurysm and dissection (TAAD) is the most fatal macro vascular disease. The mortality of 48h after diagnosis of dissection is up to approximately 50-68%. However, the genetic factors and potential mechanism underlying sporadic TAAD remain largely unknown. Our previous study suggested rs12455792 variant of

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Case-Control Studies; Cells, Cultured; Dilatation, Pathologic; Disease Models, Animal; Female; Inflammation Mediators; Macrophages; Male; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Polymorphism, Single Nucleotide; Signal Transduction; Smad4 Protein; Transforming Growth Factor beta; Vascular Remodeling

Marfan syndrome (MFS) represents a genetic disorder with variable phenotypic expression. The main cardiovascular sequelae of MFS include aortic aneurysm/dissection and cardiomyopathy. Although significant advances in the understanding of transforming growth factor beta signaling have led to promising therapeutic targets for the treatment of aortopathy, clinical studies have tempered this optimism. In particular, these studies suggest additional signaling pathways that play a significant role in disease progression. To date, studies aimed at elucidating molecular mechanisms involved in MFS-induced disease progression have been hampered by the lack of an accelerated disease model.. This accelerated murine MFS model replicates increased mortality from MFS-related maladies (20.0%, 39.3%, and 52.9% at 10, 14, and 28 days, respectively). Aortic diameters in accelerated MFS mice were significantly enlarged at 10 days after minipump implantation and correlated with a higher degree of elastin fragmentation. Accelerated MFS mice also demonstrated dilated cardiomyopathy at 14 days, even without aortic insufficiency, suggesting an intrinsic etiology.. A novel in vivo model consisting of subcutaneously delivered angiotensin II in MFS mice reproducibly causes accelerated aortic aneurysm formation and cardiomyopathy. This model allows for better investigation of MFS sequelae by rapid experimental processes.

Topics: Animals; Aortic Aneurysm, Thoracic; Cardiomyopathies; Disease Models, Animal; Disease Progression; Echocardiography; Heart Ventricles; Marfan Syndrome; Mice; Mice, Mutant Strains; Signal Transduction; Transforming Growth Factor beta

The role of TGF-β (transforming growth factor-β) signaling in abdominal aortic aneurysm (AAA) formation is controversial. Others reported that systemic blockade of TGF-β by neutralizing antibodies accelerated AAA development in angiotensin II-infused mice. This result is consistent with other studies suggesting that TGF-β signaling prevents AAA. Development of a therapy for AAA that exploits the protective actions of TGF-β would be facilitated by identification of the mechanisms through which TGF-β prevents AAA. We hypothesized that TGF-β signaling prevents AAA by its actions on aortic medial smooth muscle cells.. We compared the prevalence, severity, and histopathology of angiotensin II-induced AAA among control mice (no TGF-β blockade), mice with antibody-mediated systemic neutralization of TGF-β, and mice with genetically based smooth muscle-specific loss of TGF-β signaling. Surprisingly, we found that systemic-but not smooth muscle-specific-TGF-β blockade significantly increased the prevalence of AAA and tended to increase AAA severity, adventitial thickening, and aortic wall macrophage accumulation. In contrast, abdominal aortas of mice with smooth muscle-specific loss of TGF-β signaling differed from controls only in having a thinner media. We examined thoracic aortas of the same mice. Here we found that smooth muscle-specific loss of. Our results suggest that TGF-β signaling prevents both abdominal and thoracic aneurysmal disease but does so by distinct mechanisms. Smooth muscle extrinsic signaling protects the abdominal aorta and smooth muscle intrinsic signaling protects the thoracic aorta.

Topics: Adventitia; Angiotensin II; Animals; Antibodies; Aorta, Abdominal; Aorta, Thoracic; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Dilatation, Pathologic; Disease Models, Animal; Female; Genetic Predisposition to Disease; Male; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Phenotype; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Severity of Illness Index; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Transforming Growth Factor beta3; Tunica Media; Vascular Remodeling

Thoracic aortic aneurysm and dissection are life-threatening complications of Marfan syndrome (MFS). Studies of human and mouse aortic samples from late stage MFS demonstrate increased TGF-β activation/signaling and diffuse matrix changes. However, the role of the aortic smooth muscle cell (SMC) phenotype in early aneurysm formation in MFS has yet to be fully elucidated. As our objective, we investigated whether an altered aortic SMC phenotype plays a role in aneurysm formation in MFS. We describe previously unrecognized concordant findings in the aortas of a murine model of MFS, mgR, during a critical and dynamic phase of early development. Using Western blot, gelatin zymography, and histological analysis, we demonstrated that at postnatal day (PD) 7, before aortic TGF-β levels are increased, there is elastic fiber fragmentation/disorganization and increased levels of MMP-2 and MMP-9. Compared to wild type (WT) littermates, aortic SMCs in mgR mice express higher levels of contractile proteins suggesting a switch to a more mature contractile phenotype. In addition, tropoelastin levels are decreased in mgR mice, a finding consistent with a premature switch to a contractile phenotype. Proliferation assays indicate a decrease in the proliferation rate of mgR cultured SMCs compared to WT SMCs. KLF4, a regulator of smooth muscle cell phenotype, was decreased in aortic tissue of mgR mice. Finally, overexpression of KLF4 partially reversed this phenotypic change in the Marfan SMCs. This study indicates that an early phenotypic switch appears to be associated with initiation of important metabolic changes in SMCs that contribute to subsequent pathology in MFS.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Cell Differentiation; Cell Proliferation; Elastic Tissue; Extracellular Matrix; Gene Expression Regulation; Humans; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Marfan Syndrome; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Transgenic; Myocytes, Smooth Muscle; Phenotype; Primary Cell Culture; Signal Transduction; Transforming Growth Factor beta; Tropoelastin

Ascending thoracic aortic aneurysm (ATAA) is a major cause of morbidity and mortality worldwide. The pathogenesis of medial degeneration of the aorta remains undefined. High-throughput secretome analysis by mass spectrometry may be useful to elucidate the molecular mechanisms involved in aneurysm formation as well as to identify biomarkers for early diagnosis or targets of therapy. The purpose of the present study was to analyze the secreted/released proteins from ATAA specimens of both tricuspid aortic valve (TAV) and bicuspid aortic valve (BAV) patients.. Aortic specimens were collected from patients undergoing elective surgery and requiring graft replacement of the ascending aorta. Each sample of the ascending aortic aneurysm, 4 BAV (3 males; aged 53.5±11.4 years) and 4 TAV (1 male; 78±7.5 years), was incubated for 24h in serum-free medium. Released proteins were digested with trypsin. Peptide mixtures were fractioned by nano-high performance liquid chromatography and analyzed by mass spectrometry. Following identification of differentially expressed proteins, quantitative real time polymerase chain reaction (qRT-PCR) analysis was performed.. The comparison between the proteins released from BAV and TAV aneurysmatic tissues showed significantly diverging expression fingerprints in the two groups of patients. Bioinformatics analysis revealed 38 differentially released proteins; in particular 7 proteins were down-regulated while 31 were up-regulated in BAV with respect to TAV. Most of the proteins that were up-released in BAV were related to the activation of transforming growth factor (TGF)-β signaling. Latent TGF-β binding protein 4 (LTBP4) exhibited one of the highest significant under-expressions (10-fold change) in BAV secretomes with respect to TAV. qRT-PCR analysis validated this significant difference at LTBP4 gene level (BAV: 1.03±0.9 vs TAV: 3.6±3.2; p<0.05).. Hypothesis-free secretome profiling clearly showed diverging expression fingerprints in the ATAA of TAV and BAV patients, confirming the crucial role of TGF-β signaling in modulating ATAA development in bicuspid patients.

Topics: Aged; Aorta; Aortic Aneurysm; Aortic Aneurysm, Thoracic; Aortic Valve; Bicuspid Aortic Valve Disease; Female; Heart Valve Diseases; Humans; Latent TGF-beta Binding Proteins; Male; Middle Aged; Signal Transduction; Transforming Growth Factor beta; Tricuspid Valve

Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families.. We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed.. We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-β signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture.. In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-β signaling.Genet Med 19 4, 386-395.

Topics: Aortic Aneurysm, Thoracic; Aortic Dissection; Biglycan; Cells, Cultured; Female; Genes, X-Linked; Genetic Predisposition to Disease; Humans; Male; Mutation; Pedigree; Sequence Analysis, DNA; Signal Transduction; Transforming Growth Factor beta

Marfan syndrome (MFS) is caused by mutations in the gene encoding fibrillin-1 (FBN1); however, the mechanisms through which fibrillin-1 deficiency causes MFS-associated aortopathy are uncertain. Recently, attention was focused on the hypothesis that MFS-associated aortopathy is caused by increased transforming growth factor-β (TGF-β) signaling in aortic medial smooth muscle cells (SMC). However, there are many reasons to doubt that TGF-β signaling drives MFS-associated aortopathy. We used a mouse model to test whether SMC TGF-β signaling is perturbed by a fibrillin-1 variant that causes MFS and whether blockade of SMC TGF-β signaling prevents MFS-associated aortopathy.. MFS mice (Fbn1. In young Fbn1

Topics: Animals; Aorta; Aortic Aneurysm, Thoracic; Aortic Diseases; Disease Models, Animal; Fibrillin-1; Marfan Syndrome; Mice; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

Topics: Aorta, Thoracic; Aortic Aneurysm, Thoracic; Genetic Predisposition to Disease; Humans; Transforming Growth Factor beta; Transforming Growth Factors

AngII and TGF-β interact in development of thoracic and abdominal aortic diseases, although there are many facets of this interaction that have not been clearly defined. The aim of the present study was to determine the effects of TGF-β neutralization on AngII induced-aortic pathologies. Male C57BL/6J mice were administered with either a rabbit or mouse TGF-β neutralizing antibody and then infused with AngII. The rabbit TGF-β antibody modestly reduced serum TGF-β concentrations, with no significant enhancements to AngII-induced aneurysm or rupture. Administration of this rabbit TGF-β antibody in mice led to high serum titers against rabbit IgG that may have attenuated the neutralization. In contrast, a mouse TGF-β antibody (1D11) significantly increased rupture in both the ascending and suprarenal aortic regions, but only at doses that markedly decreased serum TGF-β concentrations. High doses of 1D11 antibody significantly increased AngII-induced ascending and suprarenal aortic dilatation. To determine whether TGF-β neutralization had effects in mice previously infused with AngII, the 1D11 antibody was injected into mice that had been infused with AngII for 28 days and were observed during continued infusion for a further 28 days. Despite near ablations of serum TGF-β concentrations, the mouse TGF-β antibody had no effect on aortic rupture or dimensions in either ascending or suprarenal region. These data provide further evidence that AngII-induced aortic rupture is enhanced greatly by TGF-β neutralization when initiated before pathogenesis.

Topics: Angiotensin II; Animals; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Aortic Rupture; Male; Mice; Mice, Inbred C57BL; Transforming Growth Factor beta

To identify differentially expressed proteins from the aortic tissue of thoracic aortic dissection (TAD) with hypertension and normal aorta and to explore the potential molecular pathogenesis of TAD.. Aortic tissue samples were collected from two groups of age- and gender-matched patients with TAD and normal aorta. These samples were subjected to isobaric tags for relative and absolute quantitation analysis to identify the proteins involved in TAD. Signalling pathways were analysed using the Metacore software, and the identified proteins were validated by western blotting.. A total of 36 proteins were identified between two groups, with 19 of them being significantly down-regulated and 17 up-regulated in patients with TAD. Proteins including fibrillin-1, emilin-1, decorin, protein DJ-1 and histone H4 were validated by western blotting. The enrichment analysis performed using the Metacore process networks data showed that cell adhesion_cell-matrix interactions, proteolysis_extracellular matrix (ECM) remodelling and inflammation_interleukin 6 (IL-6) signalling were the main protein interaction networks involved in TAD. We further observed indications of increased transforming growth factor-β (TGF-β) signalling and impaired aortic wall remodelling, both of which may be molecular mechanisms for the pathogenesis of TAD.. The differentially expressed proteins identified in our study are mainly involved in cell-matrix interaction, ECM remodelling and inflammation. These mechanisms, combined with the TGF-β signalling pathway, may play an important role in the pathogenesis of TAD.

Topics: Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Humans; Isotope Labeling; Protein Interaction Maps; Proteome; Proteomics; Signal Transduction; Transforming Growth Factor beta

Studies of mice with mild Marfan syndrome (MFS) have correlated the development of thoracic aortic aneurysm (TAA) with improper stimulation of noncanonical (Erk-mediated) TGFβ signaling by the angiotensin type I receptor (AT1r). This correlation was largely based on comparable TAA modifications by either systemic TGFβ neutralization or AT1r antagonism. However, subsequent investigations have called into question some key aspects of this mechanism of arterial disease in MFS. To resolve these controversial points, here we made a head-to-head comparison of the therapeutic benefits of TGFβ neutralization and AT1r antagonism in mice with progressively severe MFS (Fbn1(mgR/mgR) mice).. Aneurysm growth, media degeneration, aortic levels of phosphorylated Erk and Smad proteins and the average survival of Fbn1(mgR/mgR) mice were compared after a ≈3-month-long treatment with placebo and either the AT1r antagonist losartan or the TGFβ-neutralizing antibody 1D11. In contrast to the beneficial effect of losartan, TGFβ neutralization either exacerbated or mitigated TAA formation depending on whether treatment was initiated before (postnatal day 16; P16) or after (P45) aneurysm formation, respectively. Biochemical evidence-related aneurysm growth with Erk-mediated AT1r signaling, and medial degeneration with TGFβ hyperactivity that was in part AT1r dependent. Importantly, P16-initiated treatment with losartan combined with P45-initiated administration of 1D11 prevented death of Fbn1(mgR/mgR) mice from ruptured TAA.. By demonstrating that promiscuous AT1r and TGFβ drive partially overlapping processes of arterial disease in MFS mice, our study argues for a therapeutic strategy against TAA that targets both signaling pathways although sparing the early protective role of TGFβ.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antibodies, Neutralizing; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Rupture; Disease Models, Animal; Disease Progression; Fibrillin-1; Fibrillins; Humans; Losartan; Marfan Syndrome; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Mutant Strains; Microfilament Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mutation; Phosphorylation; Receptor, Angiotensin, Type 1; Signal Transduction; Smad2 Protein; Time Factors; Transforming Growth Factor beta

Aortic aneurysm, focal dilation of the aorta, results from impaired integrity of aortic extracellular matrix (ECM). Matrix metalloproteinases (MMPs) are traditionally known as ECM-degrading enzymes. MMP2 has been associated with aneurysm in patients and in animal models. We investigated the role of MMP2 in thoracic aortic aneurysm using 2 models of aortic remodeling and aneurysm.. Male 10-week-old MMP2-deficient (MMP2(-/-)) and wild-type mice received angiotensin II (Ang II, 1.5 mg/kg/day) or saline (Alzet pump) for 4 weeks. Although both genotypes exhibited dilation of the ascending aorta after Ang II infusion, MMP2(-/-) mice showed more severe dilation of the thoracic aorta and thoracic aortic aneurysm. The Ang II-induced increase in elastin and collagen (mRNA and protein) was markedly suppressed in MMP2(-/-) thoracic aorta and smooth muscle cells, whereas only mRNA levels were reduced in MMP2(-/-)-Ang II abdominal aorta. Consistent with the absence of MMP2, proteolytic activities were lower in MMP2(-/-)-Ang II compared with wild-type-Ang II thoracic and abdominal aorta. MMP2-deficiency suppressed the activation of latent transforming growth factor-β and the Smad2/3 pathway in vivo and in vitro. Intriguingly, MMP2(-/-) mice were protected against CaCl2-induced thoracic aortic aneurysm, which triggered ECM degradation but not synthesis.. This study reveals the dual role of MMP2 in ECM degradation, as well as ECM synthesis. Moreover, the greater susceptibility of the thoracic aorta to impaired ECM synthesis, compared with vulnerability of the abdominal aorta to aberrant ECM degradation, provides an insight into the regional susceptibility of the aorta to aneurysm development.

Topics: Angiotensin II; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Calcium Chloride; Cells, Cultured; Collagen; Dilatation, Pathologic; Disease Models, Animal; Elastin; Genotype; Male; Matrix Metalloproteinase 2; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; RNA, Messenger; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta; Ultrasonography; Vascular Remodeling

Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, caused by mutations of the microfibrillar protein fibrillin-1, that predisposes affected individuals to aortic aneurysm and rupture and is associated with increased TGFβ signaling. TGFβ is secreted from cells as a latent complex consisting of TGFβ, the TGFβ propeptide, and a molecule of latent TGFβ binding protein (LTBP). Improper extracellular localization of the latent complex can alter active TGFβ levels, and has been hypothesized as an explanation for enhanced TGFβ signaling observed in MFS. We previously reported the absence of LTBP-3 in matrices lacking fibrillin-1, suggesting that perturbed TGFβ signaling in MFS might be due to defective interaction of latent TGFβ complexes containing LTBP-3 with mutant fibrillin-1 microfibrils. To test this hypothesis, we genetically suppressed Ltbp3 expression in a mouse model of progressively severe MFS. Here, we present evidence that MFS mice lacking LTBP-3 have improved survival, essentially no aneurysms, reduced disruption and fragmentation of medial elastic fibers, and decreased Smad2/3 and Erk1/2 activation in their aortas. These data suggest that, in MFS, improper localization of latent TGFβ complexes composed of LTBP-3 and TGFβ contributes to aortic disease progression.

Topics: Analysis of Variance; Animals; Aortic Aneurysm, Thoracic; DNA, Complementary; Fibrillin-1; Fibrillins; Immunohistochemistry; Latent TGF-beta Binding Proteins; Marfan Syndrome; Mice; Microfilament Proteins; Multiprotein Complexes; Muscle, Smooth, Vascular; Real-Time Polymerase Chain Reaction; Transforming Growth Factor beta

In Marfan Syndrome (MFS), development of thoracic aortic aneurysms (TAAs) is characterized by degeneration of the medial layer of the aorta, including fragmentation and loss of elastic fibers, phenotypic changes in the smooth muscle cells, and an increase in the active form of transforming growth factor-β (TGFβ), which is thought to play a major role in development and progression of the aneurysm. We hypothesized that regional difference in elastic fiber fragmentation contributes to TGFβ activation and hence the localization of aneurysm formation. The fibrillin-1-deficient mgR/mgR mouse model of MFS was used to investigate regional changes in elastin fiber fragmentation, TGFβ activation and changes in gene expression as compared to wild-type littermates. Knockdown of Smad 2 and Smad 3 with shRNA was used to determine the role of the specific transcription factors in gene regulation in aortic smooth muscle cells. We show increased elastin fiber fragmentation in the regions associated with aneurysm formation and altered TGFβ signaling in these regions. Differential effects of Smad 2 and Smad 3 were observed in cultured smooth muscle cells by shRNA-mediated knockdown of expression of these transcription factors. Differential signaling through Smad 2 and Smad 3 in regions of active vascular remodeling likely contribute to aneurysm formation in the mgR/mgR model of MFS. Increased elastin fiber fragmentation in these regions is associated with these changes as compared to other regions of the thoracic aorta and may contribute to the changes in TGFβ signaling in these regions.

Topics: Animals; Aorta; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Disease Models, Animal; Disease Progression; Elastic Tissue; Gene Expression Regulation; Gene Knockdown Techniques; Marfan Syndrome; Mice, 129 Strain; Mice, Inbred C57BL; Organ Specificity; Phosphorylation; RNA, Small Interfering; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Aortic Rupture; Glycosaminoglycans; Humans; Transforming Growth Factor beta

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Aortic Rupture; Glycosaminoglycans; Humans; Transforming Growth Factor beta

Thoracic aortic aneurysm/dissection (TAAD) is a common phenotype that may occur as an isolated manifestation or within the constellation of a defined syndrome. In contrast to syndromic TAAD, the elucidation of the genetic basis of isolated TAAD has only recently started. To date, defects have been found in genes encoding extracellular matrix proteins (fibrillin-1, FBN1; collagen type III alpha 1, COL3A1), proteins involved in transforming growth factor beta (TGFβ) signaling (TGFβ receptor 1 and 2, TGFBR1/2; and SMAD3) or proteins that build up the contractile apparatus of aortic smooth muscle cells (myosin heavy chain 11, MYH11; smooth muscle actin alpha 2, ACTA2; and MYLK).. In 110 non-syndromic TAAD patients that previously tested negative for FBN1 or TGFBR1/2 mutations, we identified 7 ACTA2 mutations in a cohort of 43 familial TAAD patients, including 2 premature truncating mutations. Sequencing of MYH11 revealed an in frame splice-site alteration in one out of two probands with TAA(D) associated with PDA but none in the series of 22 probands from the cohort of 110 patients with non-syndromic TAAD. Interestingly, immunohistochemical staining of aortic biopsies of a patient and a family member with MYH11 and patients with ACTA2 missense mutations showed upregulation of the TGFβ signaling pathway.. MYH11 mutations are rare and typically identified in patients with TAAD associated with PDA. ACTA2 mutations were identified in 16% of a cohort presenting familial TAAD. Different molecular defects in TAAD may account for a different pathogenic mechanism of enhanced TGFβ signaling.

Topics: Actins; Adolescent; Adult; Aged; Aged, 80 and over; Aortic Aneurysm, Thoracic; Aortic Dissection; Cohort Studies; Female; Humans; Male; Middle Aged; Mutation; Myosin Heavy Chains; Pedigree; Signal Transduction; Transforming Growth Factor beta; Up-Regulation

Marfan syndrome (MFS) is an inherited disorder of connective tissue caused by mutations in the gene for fibrillin-1 (FBN1). The complex pathogenesis of MFS involves changes in transforming growth factor beta (TGF-β) signaling and increased matrix metalloproteinase (MMP) expression. Fibrillin-1 and elastin have repeated Gly-x-x- Pro-Gly (GxxPG) motifs that can induce a number of effects including macrophage chemotaxis and increased MMP activity by induction of signaling through the elastin-binding protein (EBP). In this work, we test the hypothesis that antagonism of GxxPG fragments can suppress disease progression in the Marfan aorta. Fibrillin-1 underexpressing mgR/mgR Marfan mice were treated with weekly intraperitoneal (i.p.) injections of an antibody directed against GxxPG fragments. The treatment was started at 3 weeks of age and continued for 8 weeks. The treatment significantly reduced MMP-2, MMP-9 and pSmad2 activity, as well as fragmentation and macrophage infiltration in the aorta of the mgR/mgR mice. Additionally, airspace enlargement and increased pSmad2 activity in the lungs of mgR/mgR animals were prevented by the treatment. Our findings demonstrate the important role of secondary cellular events caused by GxxPG-containing fragments and matrix-induced inflammatory activity in the pathogenesis of thoracic aortic aneurysm (TAA) in mgR/mgR mice. Moreover, the results of the current study suggest that antagonism of the effects of GxxPG fragments may be a fruitful therapeutic strategy in MFS.

Topics: Amino Acid Motifs; Animals; Antibodies, Monoclonal; Aortic Aneurysm, Thoracic; Aortic Diseases; Blotting, Western; Disease Models, Animal; Elastin; Enzyme-Linked Immunosorbent Assay; Fibrillin-1; Fibrillins; Immunohistochemistry; Latent TGF-beta Binding Proteins; Macrophages; Marfan Syndrome; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Microfilament Proteins; Mutation; Peptides; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta; Up-Regulation

Dilation or aneurysm of the ascending aorta can progress to acute aortic dissection (Thoracic Aortic Aneurysms and Aortic Dissections, TAAD). Mutations in genes encoding TGF-β-related proteins (TGFBR1, TGFBR2, FBN1, and SMAD3) cause syndromic and inherited TAAD. SMAD4 mutations are associated with juvenile polyposis syndrome (JPS) and a combined JPS-hereditary hemorrhagic telangiectasia (HHT) known as JPS-HHT. A family with JPS-HHT was reported to have aortic root dilation and mitral valve abnormalities. We report on two patients with JPS-HHT with SMAD4 mutations associated with thoracic aortic disease. The first patient, an 11-year-old boy without Marfan syndrome features, had JPS and an apparently de novo SMAD4 mutation (c.1340_1367dup28). Echocardiography showed mild dilation of the aortic annulus and aortic root, and mild dilation of the sinotubular junction and ascending aorta. Computed tomography confirmed aortic dilation and showed small pulmonary arteriovenous malformations (PAVM). The second patient, a 34-year-old woman with colonic polyposis, HHT, and features of Marfan syndrome, had a SMAD4 mutation (c.1245_1248delCAGA). Echocardiography showed mild aortic root dilation. She also had PAVM and hepatic focal nodular hyperplasia. Her family history was significant for polyposis, HHT, thoracic aortic aneurysm, and dissection and skeletal features of Marfan syndrome in her father. These two cases confirm the association of thoracic aortic disease with JPS-HHT resulting from SMAD4 mutations. We propose that the thoracic aorta should be screened in patients with SMAD4 mutations to prevent untimely death from dissection. This report also confirms that SMAD4 mutations predispose to TAAD.

Topics: Adult; Aorta; Aortic Aneurysm, Thoracic; Child; Echocardiography; Female; Fibrillin-1; Fibrillins; Humans; Intestinal Polyposis; Male; Marfan Syndrome; Microfilament Proteins; Mutation; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad3 Protein; Smad4 Protein; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta

The precise pathologic mechanisms underlying human thoracic aortic aneurysms (TAAs) remain uncertain, except that matrix metalloproteinase-9 (MMP-9) is considered a key enzyme for the degradation of extracellular matrix in aneurysm walls. The aim of this study was to elucidate the significance of the angiotensin II (AngII) pathway to MMP-9 production in human TAA walls.. We examined the activation of Smad2, a common downstream molecule of AngII and transforming growth factor β (TGF-β) pathways, and the expression of MMP-9 in human nonsyndromic TAA walls. We observed significant increases in Smad2 activation and MMP-9 expression, associated with disruption of elastic lamellae. Using human TAA walls in ex vivo culture, we investigated whether AngII and/or TGF-β pathways are essential for MMP-9 production. Unexpectedly, TGF-β receptor inhibitor had no effect on MMP-9 production. We used PD98059, an inhibitor of extracellular signal-regulated kinase (ERK) activation, and demonstrated that PD98059 dramatically reduced MMP-9 production with attenuation of Smad2 activation. Moreover, exogenous AngII resulted in increases in Smad2 activation and MMP-9 production, in an ERK-dependent manner.. Our findings indicate that the AngII/ERK pathway has an important role in the production of MMP-9 in human nonsyndromic TAA walls.

Topics: Angiotensin II; Aortic Aneurysm, Thoracic; Humans; MAP Kinase Signaling System; Matrix Metalloproteinase 9; Smad2 Protein; Transforming Growth Factor beta; Up-Regulation

Impaired regulation of the transforming growth factor-β (TGFβ) signaling pathway has been linked to thoracic aortic aneurysm (TAA). Previous work has indicated that differential splicing is a common phenomenon, potentially influencing the function of proteins. In the present study we investigated the occurrence of differential splicing in the TGFβ pathway associated with TAA in patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV). Affymetrix human exon arrays were applied to 81 intima/media tissue samples from dilated (n = 51) and nondilated (n = 30) aortas of TAV and BAV patients. To analyze the occurrence of alternative splicing in the TGFβ pathway, multivariate techniques, including principal component analysis and OPLS-DA (orthogonal partial least squares to latent structures discriminant analysis), were applied on all exons (n = 614) of the TGFβ pathway. The scores plot, based on the splice index of individual exons, showed separate clusters of patients with both dilated and nondilated aorta, thereby illustrating the potential importance of alternative splicing in TAA. In total, differential splicing was detected in 187 exons. Furthermore, the pattern of alternative splicing is clearly differs between TAV and BAV patients. Differential splicing was specific for BAV and TAV patients in 40 and 86 exons, respectively, and splicings of 61 exons were shared between the two phenotypes. The occurrence of differential splicing was demonstrated in selected genes by reverse transcription-polymerase chain reaction. In summary, alternative splicing is a common feature of TAA formation. Our results suggest that dilatation in TAV and BAV patients has different alternative splicing fingerprints in the TGFβ pathway.

Topics: Alternative Splicing; Aorta; Aortic Aneurysm, Thoracic; Dilatation, Pathologic; Exome; Exons; Gene Expression Profiling; Genetic Variation; Humans; Mitral Valve; Multivariate Analysis; Oligonucleotide Array Sequence Analysis; Principal Component Analysis; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transcriptome; Transforming Growth Factor beta; Tricuspid Valve

Losartan potassium (INN losartan), an antihypertensive drug, has been shown to prevent thoracic aortic aneurysm in Marfan syndrome through the inhibition of transforming growth factor beta. Recently we reported that doxycycline, a nonspecific inhibitor of matrix metalloproteinases 2 and 9, normalized aortic vasomotor function and suppressed aneurysm growth. We hypothesized that a combination of losartan potassium and doxycycline would offer better secondary prevention treatment than would single-drug therapy to manage thoracic aortic aneurysm.. A well-characterized mouse model of Marfan syndrome (Fbn1(C1039G/+)) was used. At 4 months of age, when aneurysm had established, mice (n = 15/group) were given doxycycline alone (0.24 g/L), losartan potassium alone (0.6 g/L), or combined (0.12-g/L doxycycline and 0.3-g/L losartan potassium) in drinking water. Littermate Fbn1(+/+) mice served as control. Thoracic aortas at 6 and 9 months were studied.. At 9 months, aortic diameter in untreated group was increased by 40% relative to control. Losartan potassium or doxycycline reduced aortic diameter by 10% to 16% versus untreated aortas. Losartan potassium and doxycycline combined completely prevented thoracic aortic aneurysm and improved elastic fiber organization, also downregulating matrix metalloproteinases 2 and 9 and transforming growth factor beta and normalizing aortic contractile and relaxation functions to control values.. Neither losartan potassium nor doxycycline alone completely restored vascular integrity and cell function when given during delayed treatment, indicating the importance of timed pharmacologic intervention. Combined, however, they synergistically offered better aneurysm-suppressing effects than did single-drug medication in the secondary prevention of thoracic aortic aneurysm.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Disease Models, Animal; Doxycycline; Drug Synergism; Drug Therapy, Combination; Elastic Tissue; Fibrillin-1; Fibrillins; Losartan; Marfan Syndrome; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microfilament Proteins; Phosphorylation; Protease Inhibitors; Secondary Prevention; Smad2 Protein; Time Factors; Transforming Growth Factor beta; Vasoconstriction; Vasodilation

We imaged the protease activity of matrix metalloproteinases (MMPs) upregulated during aneurysm formation, using protease-activatable near-infrared fluorescence probes. We tested whether these protease-activatable sensors can directly report the in vivo activity of the key biomarkers in aneurysm, using our genetically modified fibulin-4 mouse models for aneurysm formation. Mice homozygous for the fibulin-4 reduced-expression allele (fibulin-4(R/R)) show dilatation of the ascending aorta and a tortuous, stiffened aorta resulting from disorganized elastic fiber networks. Strikingly, even a moderate reduction in expression of fibulin-4 in the heterozygous fibulin-4(+/R) mice occasionally results in modest aneurysm formation.. Aorta transcriptome and protein expression analysis of fibulin-4(+/R) and fibulin-4(R/R) animals identified excessive transforming growth factor-β signaling as the critical event in the pathogenesis of aneurysm formation. To determine whether a perturbed elastin lamellar structure arose from induction of transforming growth factor-β-regulated MMPs, we performed gelatin zymography and used a protease-activatable near-infrared fluorescence probe to monitor and quantify MMP upregulation in animals, using various in vivo optical imaging modules and coregistration of the fluorescence signal with CT images of the same animals. Gelatin zymography demonstrated a significant increase in the presence of the active form of MMP-9 in the aortic arch of fibulin-4(R/R) mice. In vivo analysis of MMP upregulation using the near-infrared fluorescence probe and subsequent isosurface concentration mapping from reconstructed tomographic images from fibulin-4(+/R) and fibulin-4(R/R) mice revealed a graded increase in activation of MMPs within the aneurysmal lesions.. We aimed to develop molecular imaging procedures for faster, earlier, and easier recognition of aortic aneurysms. We show that in vivo coregistration of MMP activity by noninvasive tomographic imaging methods allows the detection of increased MMP activity, even before the aneurysm has actually formed.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortography; Biomarkers; Biosensing Techniques; Disease Models, Animal; Disease Progression; Early Diagnosis; Elastin; Enzyme Activation; Extracellular Matrix Proteins; Fluorescence; Magnetic Resonance Angiography; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Imaging; Predictive Value of Tests; Signal Transduction; Spectroscopy, Near-Infrared; Tomography, X-Ray Computed; Transforming Growth Factor beta; Up-Regulation

Thoracic ascending aortic aneurysms (TAA) are characterized by elastic fibre breakdown and cystic medial degeneration within the aortic media, associated with progressive smooth muscle cell (SMC) rarefaction. The transforming growth factor (TGF)-β/Smad2 signalling pathway is involved in this process. Because the pericellular fibrinolytic system activation is able to degrade adhesive proteins, activate matrix metalloproteinase (MMP), induce SMC disappearance and increase the bioavailability of TGF-β, the aim was to investigate the plasminergic system in TAA.. Ascending aortas [21 controls and 19 TAAs (of three different aetiologies)] were analysed. Immunohistochemistry showed accumulation of t-PA, u-PA and plasmin in TAAs, associated with residual SMCs. Overexpression of t-PA and u-PA was confirmed by reverse transcription-polymerase chain reaction (RT-PCR), immunoblotting and zymography on TAA extracts and culture medium conditioned by TAA. Plasminogen was present on the SMC surface and inside cytoplasmic vesicles, but plasminogen mRNA was undetectable in the TAA medial layer. Plasmin-antiplasmin complexes were detected in TAA-conditioned medium and activation of the fibrinolytic system was associated with increased fibronectin turnover. Fibronectin-related material was detected immunohistochemically in dense clumps around SMCs and colocalized with latent TGF-β binding protein-1.. The fibrinolytic pathway could play a critical role in TAA progression, via direct or indirect impact on ECM and consecutive modulation of TGF-β bioavailability.

Topics: Adult; Aged; Aorta; Aortic Aneurysm, Thoracic; Blotting, Western; Female; Humans; Immunohistochemistry; Male; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Smad2 Protein; Tissue Plasminogen Activator; Transforming Growth Factor beta; Urokinase-Type Plasminogen Activator

Loeys-Dietz syndrome (LDS) is a recently described genetic aortic aneurysm syndrome resulting from mutations in receptors for the cytokine transforming growth factor-beta. Phenotypic features include a bifid uvula, hypertelorism, cleft palate, and generalized arterial tortuosity, but risk of thoracic aortic rupture and dissection is the principle focus of management and exceeds that of most known connective tissue disorders. Our surgical experience with LDS was reviewed to assess outcomes and develop guidelines for management of this aggressive disease.. We retrospectively reviewed medical records of all LDS patients from two institutions and obtained follow-up data from medical records and patient contacts.. Clinical criteria and genotyping were used to identify 71 patients. Before surgical intervention, 6 patients (9%) died from aneurysm rupture or dissection, which occurred in several patients with aortic diameters of less than 4.5 cm and as early as 6 months of age. Thoracic aortic aneurysm surgery was performed in 14 children and 7 adults. Operations included valve-sparing root replacement (VSRR) in 13, Bentall procedure in 5, arch replacement in 2, and VSRR with arch replacement in 1. There were no deaths at the primary operation, although 3 patients died 2, 5, and 11 years after surgery from rupture of the descending thoracic (n = 2) or abdominal aorta (n = 1).. LDS is an aggressive aortic aneurysm disease with a propensity toward rupture and dissection at a younger age and smaller aortic diameters than in other connective tissue disorders, particularly in the ascending aorta. Early recognition of the phenotype, prophylactic intervention, and meticulous surveillance of the distal aorta and vascular tree are warranted for optimal management.

Topics: Adolescent; Adult; Aorta, Thoracic; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Aortic Rupture; Blood Vessel Prosthesis Implantation; Child; Child, Preschool; Cohort Studies; Female; Genotype; Humans; Infant; Male; Mutation; Phenotype; Retrospective Studies; Severity of Illness Index; Syndrome; Transforming Growth Factor beta

Marfan syndrome (MFS) is known to cause ascending thoracic aortic aneurysms (ATAAs). Transforming growth factor beta (TGF-beta) has recently been implicated in this process. Imbalances between the matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) have also been shown to contribute to aneurysm formation. Whether and to what degree MMP, TIMP, and TGF-beta signaling profiles are altered in ATAAs in MFS compared with non-MFS patients remains unknown.. ATAA samples taken during aortic replacement from age-matched MFS (n=9) and non-MFS (n=18) patients were assessed for representative subtypes of all MMP classes, all 4 known TIMPs, and type 2 TGF-beta receptors (TGFBR2). Results were expressed as a percentage (mean+/-SEM) of reference control samples (100%; n=18) obtained from patients without ATAA. In MFS, decreased MMP-2 (76+/-7; P<0.05 versus control), increased MMP-12 (161+/-27% versus control; P<0.05), and increased MT1-MMP (248+/-64% versus 91+/-21 non-MFS and control; P<0.05) were observed. TIMP-3 (74+/-23%) was reduced compared with control values (P<0.05) and TIMP-2 was elevated (128+/-31%) compared with non-MFS (73+/-19%; P<0.05). In non-MFS samples, MMP-1 (70+/-16%), MMP-3 (77+/-18%), MMP-8 (75+/-11%), MMP-9 (69+/-14%), and MMP-12 (85+/-15%) were decreased compared with control (P<0.05). TIMPs 1 to 3 were reduced in non-MFS compared with control values (P<0.05). TGFBR2 were increased in MFS (193+/-32%) compared with non-MFS (95+/-16%) and controls (P<0.05).. A unique MMP and TIMP portfolio was observed in ATAAs from MFS compared with non-MFS patients. In addition, MFS samples showed evidence of increased TGF-beta signaling. These differences suggest disparate mechanisms of extracellular matrix remodeling between these 2 groups of patients.

Topics: Adult; Aorta; Aortic Aneurysm, Thoracic; Aortic Dissection; Blood Vessel Prosthesis Implantation; Disease Susceptibility; Female; Fibrillins; Gene Expression Profiling; Gene Expression Regulation; Humans; Male; Marfan Syndrome; Matrix Metalloproteinases; Matrix Metalloproteinases, Membrane-Associated; Microfilament Proteins; Middle Aged; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta

Monocyte CD14 and its soluble form (sCD14) mediate the proinflammatory response to endotoxemia. The aim of this study was to measure the changes to these factors after major aortic surgery and the possible inhibitory role of transforming growth factor-beta(1) (TGF-beta(1)) during these procedures.. Twenty-four patients with supraceliac aortic crossclamping during thoracoabdominal aortic aneurysm (TAAA) repair and 12 patients with infrarenal aortic crossclamping as part of infrarenal aneurysm repair (AAA) were studied. Blood was collected at incision, aortic clamping, and reperfusion and at 1, 8, and 24 hours after reperfusion. Samples were assayed for endotoxin, peripheral blood monocyte CD14 expression, sCD14, tumor necrosis factor-alpha, and TGF-beta(1).. Although there was significant endotoxemia on reperfusion in both groups of patients, peak plasma endotoxin levels were significantly higher in patients with TAAA (P =.001). Monocyte CD14 and plasma sCD14 were significantly decreased in patients with TAAA at reperfusion and 1 hour after reperfusion (P <.01, both points). In patients with AAA, a significant upregulation of CD14 was observed at 24 hours after reperfusion (P <.01), but no significant changes in sCD14 were observed. TNF-alpha showed no significant changes during the study period in both groups. In patients with TAAA, TGF-beta(1) showed significant elevation at all time points (P <.01); whereas in patients with AAA, TGF-beta(1) showed no significant changes.. Splanchnic ischemia reperfusion in patients who undergo supraceliac aortic clamping is associated with peripheral blood monocyte CD14 suppression and significant elevation of TGF-beta(1). TGF-beta(1) may play an important role in modulating the immune response to endotoxemia during major aortic aneurysm surgery.

Topics: Aged; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Endotoxemia; Female; Humans; Immune Tolerance; Intraoperative Period; Leukocytes, Mononuclear; Lipopolysaccharide Receptors; Male; Reperfusion; Splanchnic Circulation; Transforming Growth Factor beta