transforming-growth-factor-beta and Dilatation--Pathologic

Dilatation of the aorta is a constantly evolving condition that can lead to the ultimate life-threatening event, acute aortic dissection. Recent research has tried to identify quantifiable biomarkers, with both diagnostic and prognostic roles in different aortopathies. Most studies have focused on the bicuspid aortic valve, the most frequent congenital heart disease (CHD), and majorly evolved around matrix metalloproteinases (MMPs). Other candidate biomarkers, such as asymmetric dimethylarginine, soluble receptor for advanced glycation end-products or transforming growth factor beta have also gained a lot of attention recently. Most of the aortic anomalies and dilatation-related studies have reported expression variation of tissular biomarkers. The ultimate goal remains, though, the identification of biomarkers among the serum plasma, with the upregulation of circulating MMP-1, MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), asymmetric dimethylarginine (ADMA), soluble receptor for advanced glycation end-products (sRAGE) and transforming growth factor beta (TGF-β) being reported in association to several aortopathies and related complications in recent research. These molecules are apparently quantifiable from the early ages and have been linked to several CHDs and hereditary aortopathies. Pediatric data on the matter is still limited, and further studies are warranted to elucidate the role of plasmatic biomarkers in the long term follow-up of potentially evolving congenital aortopathies.

Topics: Aorta; Aortic Valve; Biomarkers; Child; Dilatation, Pathologic; Heart Defects, Congenital; Heart Valve Diseases; Humans; Matrix Metalloproteinases; Receptor for Advanced Glycation End Products; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

Topics: Adolescent; Adult; Bone Morphogenetic Protein 2; Bone Screws; Dilatation, Pathologic; Dura Mater; Humans; Magnetic Resonance Imaging; Male; Neurofibromatoses; Plastic Surgery Procedures; Recombinant Proteins; Spinal Curvatures; Tomography, X-Ray Computed; Transforming Growth Factor beta

Many patients with congenital cardiac disease are at risk for progressive aortic dilation. The mechanisms underlying aortic dilation in this patient cohort are described, and the similarities to the pathophysiologic alterations seen in Marfan syndrome are highlighted. Indications for treatment are discussed.

Topics: Aortic Diseases; Dilatation, Pathologic; Heart Defects, Congenital; Humans; Marfan Syndrome; Transforming Growth Factor beta

The major clinical problem of Marfan syndrome (MFS) is the aortic root aneurysm, with risk of dissection when the root diameter approximates 5 cm. In MFS, a key molecule, transforming growth factor-beta (TGF-beta), normally bound to the extracellular matrix, is free and activated. In an experimental setting, TGF-beta blockade prevents the aortic root structural damage and dilatation. The angiotensin receptor 1 blockers (sartanics) exert an anti-TGF-beta effect; trials are now ongoing for evaluating the effect of losartan compared with atenolol in MFS. beta-Adrenergic blockers are the drugs most commonly used in MFS. The third-generation beta-adrenergic blocker nebivolol retains the beta-adrenergic blocker effects on heart rate and further exerts antistiffness effects, typically increased in MFS.. The open-label phase III study will include 291 patients with MFS and proven FBN1 gene mutations, with aortic root dilation (z-score > or =2.5). The patients will be randomized to nebivolol, losartan and the combination of the two drugs. The primary end point is the comparative evaluation of the effects of losartan, nebivolol and the association of both on the progression of aortic root growth rate. Secondary end points include the pharmacokinetics of the two drugs, comparative evaluation of serum levels of total and active TGF-beta, quantitative assessment of the expression of the mutated gene (FBN1, both 5' and 3'), pharmacogenetic bases of drug responsiveness. The quality of life evaluation in the three groups will be assessed. Statistical evaluation includes an interim analysis at month 24 and conclusive analyses at month 48.. The present study will add information about pharmacological therapy in MFS, supporting the new application of angiotensin receptor 1 blockers and finding beta-adrenergic blockers that may give more specific effects. Moreover, the study will further deepen understanding of the pathogenetic mechanisms that are active in Marfan syndrome through the pharmacogenomic and transcriptomic mechanisms that may explain MFS phenotype variability.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Angiotensin II Type 1 Receptor Blockers; Aortic Aneurysm; Benzopyrans; Child; Child, Preschool; Dilatation, Pathologic; Disease Progression; Ethanolamines; Female; Fibrillin-1; Fibrillins; Humans; Infant; Losartan; Male; Marfan Syndrome; Microfilament Proteins; Middle Aged; Mutation; Nebivolol; Quality of Life; Research Design; Time Factors; Transforming Growth Factor beta; Treatment Outcome; Young Adult

We sought to determine whether there are differences in transforming growth factor-beta (TGFß) signaling in aneurysms associated with bicuspid (BAV) and unicuspid (UAV) aortic valves versus normal aortic valves. Ascending aortic aneurysms are frequently associated with BAV and UAV. The mechanisms are not yet clearly defined, but similarities to transforming growth factor-beta TGFß vasculopathies (i.e. Marfan, Loeys-Dietz syndromes) are reported. Non-dilated (ND) and aneurysmal (D) ascending aortic tissue was collected intra-operatively from individuals with a TAV (N = 10ND, 10D), BAV (N = 7ND, 8D) or UAV (N = 7ND, 8D). TGFß signaling and aortic remodeling were assessed through immuno-assays and histological analyses. TGFß1 was increased in BAV/UAV-ND aortas versus TAV (P = 0.02 and 0.04, respectively). Interestingly, TGFß1 increased with dilatation in TAV (P = 0.03) and decreased in BAV/UAV (P = 0.001). In TAV, SMAD2 and SMAD3 phosphorylation (pSMAD2, pSMAD3) increased with dilatation (all P = 0.04) and with TGFß1 concentration (P = 0.04 and 0.03). No relationship between TGFß1 and pSMAD2 or pSMAD3 was observed for BAV/UAV (all P > 0.05). pSMAD3 increased with dilatation in BAV/UAV aortas (P = 0.01), whereas no relationship with pSMAD2 was observed (P = 0.56). Elastin breaks increased with dilatation in all groups (all P < 0.05). In TAV, elastin degradation correlated with TGFß1, pSMAD2 and pSMAD3 (all P < 0.05), whereas in BAV and UAV aortas, elastin degradation correlated only with pSMAD3 (P = 0.0007). TGFß signaling through SMAD2/SMAD3 contributes to aortic remodeling in TAV, whereas TGFß-independent activation of SMAD3 may underlie aneurysm formation in BAV/UAV aortas. Therefore, SMAD3 should be further investigated as a therapeutic target against ascending aortic dilatation in general, and particularly in BAV/UAV patients.

Topics: Aortic Diseases; Dilatation; Dilatation, Pathologic; Elastin; Heart Valve Diseases; Humans; Smad3 Protein; Transforming Growth Factor beta; Transforming Growth Factors

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Topics: Animals; Aorta; Aortic Aneurysm; Cell Adhesion Molecules; Dilatation, Pathologic; Endothelium, Vascular; Female; Male; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Muscle, Smooth, Vascular; Myosin Heavy Chains; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphoproteins; Phosphorylation; Receptor, Transforming Growth Factor-beta Type II; Signal Transduction; Transforming Growth Factor beta; Vasoconstriction

We investigated the effect of a potent TGFβ (transforming growth factor β) inhibitor peptide (P144) from the betaglycan/TGFβ receptor III on aortic aneurysm development in a Marfan syndrome mouse model.. We used a chimeric gene encoding the P144 peptide linked to apolipoprotein A-I via a flexible linker expressed by a hepatotropic adeno-associated vector. Two experimental approaches were performed: (1) a preventive treatment where the vector was injected before the onset of the aortic aneurysm (aged 4 weeks) and followed-up for 4 and 20 weeks and (2) a palliative treatment where the vector was injected once the aneurysm was formed (8 weeks old) and followed-up for 16 weeks. We evaluated the aortic root diameter by echocardiography, the aortic wall architecture and TGFβ signaling downstream effector expression of pSMAD2 and pERK1/2 by immunohistomorphometry, and Tgfβ1 and Tgfβ2 mRNA expression levels by real-time polymerase chain reaction. Marfan syndrome mice subjected to the preventive approach showed no aortic dilation in contrast to untreated Marfan syndrome mice, which at the same end point age already presented the aneurysm. In contrast, the palliative treatment with P144 did not halt aneurysm progression. In all cases, P144 improved elastic fiber morphology and normalized pERK1/2-mediated TGFβ signaling. Unlike the palliative treatment, the preventive treatment reduced Tgfβ1 and Tgfβ2 mRNA levels.. P144 prevents the onset of aortic aneurysm but not its progression. Results indicate the importance of reducing the excess of active TGFβ signaling during the early stages of aortic disease progression.

Topics: Animals; Aorta; Aortic Aneurysm; Dependovirus; Dilatation, Pathologic; Disease Models, Animal; Female; Fibrillin-1; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Male; Marfan Syndrome; Mice, Inbred C57BL; Peptide Fragments; Proteoglycans; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

Marfan syndrome (MFS) represents a genetic disorder with a range of clinical features, including proximal aortic aneurysms. Extensive research has revealed an abundance of transforming growth factor beta from a mutation in fibrillin-1 to be the key biochemical mechanism of aneurysm formation. Many important signaling pathways downstream of transforming growth factor beta have been further characterized. Our laboratory has previously demonstrated a unique murine model of MFS resulting in the accelerated formation of ascending aortic aneurysms and dilated cardiomyopathies. This study aims to characterize the relevance of this model to known signaling mechanisms in MFS.. Mice with MFS displayed downstream regulation in both the canonical (Smad2) and noncononical (extracellular signal-regulated kinases and P38) pathways characteristic of MFS. However, these downstream signals were exaggerated in the MFS mice supplemented with angiotensin II (accelerated model), matching the observed phenotypic severity of this model.. The murine MFS model depicted here accelerates ascending aortic aneurysm formation and cardiomyopathies via well-characterized MFS signaling cascades. The mechanistic relevance of the accelerated murine MFS model suggests that it could be an important tool in future studies hoping to characterize MFS signaling in an expedited experimental design.

Topics: Angiotensin II; Animals; Aorta; Aortic Aneurysm; Cardiomyopathies; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Extracellular Signal-Regulated MAP Kinases; Fibrillin-1; Genetic Predisposition to Disease; Heterozygote; Marfan Syndrome; Mice, Mutant Strains; Mutation; Myocardium; p38 Mitogen-Activated Protein Kinases; Phenotype; Phosphorylation; Signal Transduction; Smad2 Protein; Time Factors; 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

Abdominal aortic aneurysm (AAA) is an individual and socioeconomic burden in today's ageing society. Treatment relies on surgical exclusion of the dilated aorta by open or endovascular repair. For research purposes, animal models are necessary and the elastase induced aneurysm model closely mimics end stage human aneurysm disease. To improve the translational value of this model, four modifications to the classic elastase perfusion procedure (PPE) in relation to human aneurysm morphology were conducted.. In ten week old male C57BL/6J wild type mice the PPE procedure was modified in four ways using two different techniques. Flow alteration was simulated by partial ligation of the common iliac artery or the distal aorta. Additionally, careful exploration of the abdominal aortic branches allowed PPE induction at the suprarenal and iliac level. Molecular biology, ultrasound, and immunohistochemistry were used to evaluate these pilot results.. Two aortic outflow obstructions simulating distal aortic or iliac stenosis significantly increase murine AAA diameter (p = .046), and affect local vascular wall remodelling. Suprarenal aortic dissection allows a juxtarenal aneurysm to be induced, similar to the angiotensin II induced aneurysm model. A separate investigation for canonical activation of transforming growth factor β in the two embryonically distinct juxtarenal and infrarenal segments showed no distinct difference. Creating an aortoiliac bifurcated aneurysm completes the mimicry of human aneurysm morphology.. The alteration of the classic PPE aneurysm by outflow modulation and further elastase perfusion to the juxtarenal and aortoiliac segment modifies morphology and diameter, and thus increases the translational value in future research.

Topics: Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Dilatation, Pathologic; Disease Models, Animal; Hemodynamics; Iliac Artery; Ligation; Male; Mice, Inbred C57BL; Pancreatic Elastase; Phosphorylation; Regional Blood Flow; Smad2 Protein; Smad3 Protein; Time Factors; Transforming Growth Factor beta

The objective of the present study was to 1) analyze the ascending aortic proteome within a mouse model of Marfan syndrome (MFS; Fbn1

Topics: Animals; Aorta; Aortic Aneurysm; Cell Movement; Cell Proliferation; Cells, Cultured; Chromatography, High Pressure Liquid; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Fibrillin-1; Genetic Predisposition to Disease; Integrin beta3; Male; Marfan Syndrome; Mass Spectrometry; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Phenotype; Phosphorylation; Protein Serine-Threonine Kinases; Proteomics; Rapamycin-Insensitive Companion of mTOR Protein; Signal Transduction; Time 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

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

Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGFβ (transforming growth factor-β) activity-a guardian of vascular integrity and immune homeostasis-would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture.. Here, we test this hypothesis in the elastase-induced AAA model in mice. We analyze AAA development and progression using ultrasound in vivo, synchrotron-based ultrahigh resolution imaging ex vivo, and a combination of biological, histological, and flow cytometry-based cellular and molecular approaches in vitro. Systemic blockade of TGFβ using a monoclonal antibody induces a transition from a self-contained aortic dilatation to a model of sustained aneurysmal growth, associated with the formation of an intraluminal thrombus. AAA growth is associated with wall disruption but no medial dissection and culminates in fatal transmural aortic wall rupture. TGFβ blockade enhances leukocyte infiltration both in the aortic wall and the intraluminal thrombus and aggravates extracellular matrix degradation. Early blockade of IL-1β or monocyte-dependent responses substantially limits AAA severity. However, blockade of IL-1β after disease initiation has no effect on AAA progression to rupture.. Endogenous TGFβ activity is required for the healing of AAA. TGFβ blockade may be harnessed to generate new models of AAA with better relevance to the human disease. We expect that the new models will improve our understanding of the pathophysiology of AAA and will be useful in the identification of new therapeutic targets.

Topics: Animals; Antibodies, Monoclonal; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortic Rupture; Apolipoproteins E; Chemotaxis, Leukocyte; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Extracellular Matrix; Interleukin-1beta; Kinetics; Male; Mice, Inbred C57BL; Mice, Knockout; Pancreatic Elastase; Synchrotrons; Thrombosis; Transforming Growth Factor beta; Ultrasonography; Vascular Remodeling; Wound Healing

Abdominal aortic aneurysm (AAA) is a frequent, potentially life-threatening, disease that can only be treated by surgical means such as open surgery or endovascular repair. No alternative treatment is currently available, and despite expanding knowledge about the pathomechanism, clinical trials on medical aneurysm abrogation have led to inconclusive results. The heterogeneity of human AAA based on histologic examination is thereby generally neglected. In this study we aimed to further elucidate the role of these differences in aneurysm disease.. Tissue samples from AAA and popliteal artery aneurysm patients were examined by histomorphologic analysis, immunohistochemistry, Western blot, and polymerase chain reaction. The results were correlated with clinical data such as aneurysm diameter and laboratory results.. The morphology of human AAA vessel wall probes varies tremendously based on the grade of inflammation. This correlates with increasing intima/media thickness and upregulation of the vascular endothelial growth factor cascade but not with any clinical parameter or the aneurysm diameter. The phenotypic switch of vascular smooth muscle cells occurred regardless of the inflammatory state and expressional changes of the transcription factors Kruppel-like factor-4 and transforming growth factor-β lead to differential protein localization in aneurysmal compared with control arteries. These changes were in similar manner also observed in samples from popliteal artery aneurysms, which, however, showed a more homogenous phenotype.. Heterogeneity of AAA vessel walls based on inflammatory morphology does not correlate with AAA diameter yet harbors specific implications for basic research and possible aneurysm detection.

Topics: Aneurysm; Angiogenic Proteins; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortography; Biomarkers; Cell Dedifferentiation; Computed Tomography Angiography; Dilatation, Pathologic; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Inflammation; Inflammation Mediators; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Popliteal Artery; Transforming Growth Factor beta; Vascular Remodeling

It is generally agreed that the cause of a megaureter is narrowing at the vesicoureteral junction, with a functional obstruction arising from an aperistaltic, juxtavesical segment that is unable to transport urine at an acceptable rate. Histological examinations of megaureter specimens have reported several histological analyses, and the pathogenic role of transforming growth factor is still a matter of speculation.. To evaluate whether transforming growth factor-beta (TGF-β) and its receptors (TGFRs) are expressed during ureterovesical junction (UVJ) and lower ureter development in mice, and whether exogenous TGF-β might postpone the maturation of smooth muscle cells, in the pathogenesis of megaureter using an embryonic organ-culture model.. Expression of TGF-β and TGFRs on the lower ureter and UVJ were determined at different embryonic days (E) (E16, 18, 20 and postnatal day 1). The functional studies were performed by harvesting ureters from wild-type mice at embryonic day 16 (E16), which were grown in serum-free organ-culture; some cultures were supplemented with TGF-β (2 and 20 ng/ml) and/or with soluble TGFR, which blocks bioactivity. Organs were harvested after 6 days and the expression of CD31 and Ki67 were assessed using immunohistochemistry. The muscle content of the UVJ and ureter were analyzed by flowcytometry.. The TGF-β and TGFR positive cells were immune detected in embryonic ureters. The TGF-β expression was highest on E18 and decreased postnatally. Exogenous TGF-β decreased ureterovesical (UV) muscle differentiation and proliferation. The longitudinal muscle fibers were significantly less in TGF-β explants. The TGF-β also decreased the proportions of cells expressing α smooth muscle actin (α-SMA). Soluble TGFR blocked the effects of exogenous TGF-β.. In organ culture, exogenous TGF-β postpones the UV smooth muscle proliferation and affects the muscular structure. Whether the effects of TGF-β are direct or indirect, these form an in-vitro megaureter model. The finding that TGF-β is highest in embryonic ureters in vivo and decreased postnatally suggests that a pathological persistence might potentially explain the pathogenesis of primary megaureters.

Topics: Animals; Dilatation, Pathologic; Disease Models, Animal; Female; Male; Mice; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta; Ureter; Ureteral Diseases

Marfan syndrome (MFS) is a systemic connective tissue disorder that is caused by mutations of fibrillin-1. While MFS patients are at a high risk of periodontitis and aortic diseases, little causal information has been provided to date. To clarify the relationship, their oral condition and sinus of Valsalva (SoV) were evaluated.The subjects were patients with MFS (n = 33) who attended the University of Tokyo Hospital. We divided them into two groups; MFS patients with highly dilated (the diameters were equal to or more than 39 mm) SoV (high group, n = 18) and MFS patients with mildly dilated (less than 39 mm) SoV (mild group, n = 15). Blood examinations, echocardiograms, and full-mouth clinical measurements, including number of teeth, probing pocket depth (PPD), bleeding on probing (BOP), and community periodontal index (CPI) were performed.We found that the high group patients had greater rates of BOP compared to that of the mild group. Furthermore, the high group tended to have higher serum levels of C-reactive protein, matrix metalloproteinase-9, and transforming growth factor-β compared to the mild group.Periodontitis may deteriorate SoV dilatation in MFS patients.

Topics: Adult; Biomarkers; C-Reactive Protein; Dilatation, Pathologic; Female; Hospitals, University; Humans; Japan; Male; Marfan Syndrome; Matrix Metalloproteinase 9; Periodontal Index; Periodontitis; Predictive Value of Tests; Sensitivity and Specificity; Sinus of Valsalva; Transforming Growth Factor beta

Marfan's syndrome is characterized by the formation of ascending aortic aneurysms resulting from altered assembly of extracellular matrix microfibrils and chronic tissue growth factor (TGF)-β signaling. TGF-β is a potent regulator of the vascular smooth muscle cell (VSMC) phenotype. We hypothesized that as a result of the chronic TGF-β signaling, VSMC would alter their basal differentiation phenotype, which could facilitate the formation of aneurysms. This study explores whether Marfan's syndrome entails phenotypic alterations of VSMC and possible mechanisms at the subcellular level.. Immunohistochemical and Western blotting analyses of dilated aortas from Marfan patients showed overexpression of contractile protein markers (α-smooth muscle actin, smoothelin, smooth muscle protein 22 alpha, and calponin-1) and collagen I in comparison with healthy aortas. VSMC explanted from Marfan aortic aneurysms showed increased in vitro expression of these phenotypic markers and also of myocardin, a transcription factor essential for VSMC-specific differentiation. These alterations were generally reduced after pharmacological inhibition of the TGF-β pathway. Marfan VSMC in culture showed more robust actin stress fibers and enhanced RhoA-GTP levels, which was accompanied by increased focal adhesion components and higher nuclear localization of myosin-related transcription factor A. Marfan VSMC and extracellular matrix measured by atomic force microscopy were both stiffer than their respective controls.. In Marfan VSMC, both in tissue and in culture, there are variable TGF-β-dependent phenotypic changes affecting contractile proteins and collagen I, leading to greater cellular and extracellular matrix stiffness. Altogether, these alterations may contribute to the known aortic rigidity that precedes or accompanies Marfan's syndrome aneurysm formation.

Topics: Actins; Aorta; Aortic Aneurysm; Biomarkers; Calcium-Binding Proteins; Calponins; Case-Control Studies; Cell Differentiation; Cell Line, Tumor; Collagen Type I; Cytoskeletal Proteins; Dilatation, Pathologic; Focal Adhesions; Humans; Marfan Syndrome; Microfilament Proteins; Muscle Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nuclear Proteins; Phenotype; rhoA GTP-Binding Protein; Signal Transduction; Stress Fibers; Trans-Activators; Transforming Growth Factor beta; Vascular Remodeling

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

Heart failure in diabetics is associated with cardiac hypertrophy, fibrosis and diastolic dysfunction. Activation of transforming growth factor-β/Smad3 signaling in the diabetic myocardium may mediate fibrosis and diastolic heart failure, while preserving matrix homeostasis. We hypothesized that Smad3 may play a key role in the pathogenesis of cardiovascular remodeling associated with diabetes mellitus and obesity.. We generated leptin-resistant db/db Smad3 null mice and db/db Smad3+/- animals. Smad3 haploinsufficiency did not affect metabolic function in db/db mice, but protected from myocardial diastolic dysfunction, while causing left ventricular chamber dilation. Improved cardiac compliance and chamber dilation in db/db Smad3+/- animals were associated with decreased cardiomyocyte hypertrophy, reduced collagen deposition, and accentuated matrix metalloproteinase activity. Attenuation of hypertrophy and fibrosis in db/db Smad3+/- hearts was associated with reduced myocardial oxidative and nitrosative stress. db/db Smad3 null mice had reduced weight gain and decreased adiposity associated with attenuated insulin resistance, but also exhibited high early mortality, in part, because of spontaneous rupture of the ascending aorta. Ultrasound studies showed that both lean and obese Smad3 null animals had significant aortic dilation. Aortic dilation in db/db Smad3 null mice occurred despite reduced hypertension and was associated with perturbed matrix balance in the vascular wall.. Smad3 mediates diabetic cardiac hypertrophy, fibrosis, and diastolic dysfunction, while preserving normal cardiac geometry and maintaining the integrity of the vascular wall.

Topics: Animals; Aorta; Aortic Aneurysm; Aortic Rupture; Cardiomegaly; Diabetic Cardiomyopathies; Dilatation, Pathologic; Disease Models, Animal; Female; Fibrosis; Male; Matrix Metalloproteinases; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Obesity; Signal Transduction; Smad3 Protein; Time Factors; Transforming Growth Factor beta; Vascular Remodeling; Ventricular Dysfunction, Left; Ventricular Remodeling

Leptin promotes atherosclerosis and vessel wall remodeling. As abdominal aortic aneurysm (AAA) formation involves tissue remodeling, we hypothesized that local leptin synthesis initiates and promotes this process.. Human surgical AAA walls were analyzed for antigen and mRNA levels of leptin and leptin receptor, as well as mRNA for matrix metalloproteinases (MMP)-9 and MMP-12. Leptin and leptin receptor antigen were evident in all AAAs, and leptin, MMP-9, and MMP-12 mRNA was increased relative to age-matched nondilated controls. To simulate in vivo local leptin synthesis, ApoE(-/-) mice were subjected to a paravisceral periaortic application of low-dose leptin. Leptin-treated aortas exhibited decreased transforming growth factor-β and increased MMP-9 mRNA levels 5 days after surgery, and leptin receptor mRNA was upregulated by day 28. Serial ultrasonography demonstrated accelerated regional aortic diameter growth after 28 days, correlating with local medial degeneration, increased MMP-9, MMP-12, and periadventitial macrophage clustering. Furthermore, the combination of local periaortic leptin and systemic angiotensin II administration augmented medial MMP-9 synthesis and aortic aneurysm size.. Leptin is locally synthesized in human AAA wall. Paravisceral aortic leptin in ApoE(-/-) mice induces local medial degeneration and augments angiotensin II-induced AAA, thus suggesting novel mechanistic links between leptin and AAA formation.

Topics: Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Apolipoproteins E; Delayed-Action Preparations; Dilatation, Pathologic; Disease Models, Animal; Humans; Leptin; Macrophages; Male; Matrix Metalloproteinase 12; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Leptin; RNA, Messenger; Time Factors; Transforming Growth Factor beta; Ultrasonography

Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far.. Here we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6), 95% CI: 70-159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients.. In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.

Topics: Adolescent; Adult; Aorta; Cluster Analysis; Cytokines; Dilatation, Pathologic; Female; Gene Expression Profiling; Humans; Inflammation; Male; Marfan Syndrome; Middle Aged; Oligonucleotide Array Sequence Analysis; Severity of Illness Index; Transcriptome; Transforming Growth Factor beta; Young Adult

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

Post-haemorrhagic ventricular dilatation (PHVD) after intraventricular haemorrhage (IVH) remains a significant problem in preterm infants. Due to serious disadvantages of ventriculoperitoneal shunt dependence, there is an urgent need for non-surgical interventions. Considerable experimental and clinical evidence implicates transforming growth factor β (TGFβ) in the pathogenesis of PHVD. Colchicine and decorin are both compounds with anti-TGFβ properties. The former downregulates TGFβ production and is in clinical use for another fibrotic disease, and the latter inactivates TGFβ.. We hypothesized that administration of decorin or colchicine, which both have anti-TGFβ properties, would reduce ventricular dilatation in a model of PHVD.. 142 rat pups underwent intraventricular blood injection on postnatal days (PN) 7 and 8. Sixty-nine pups were randomized to colchicine 20 and 50 μg/kg/day or water by gavage for 13 days. Seventy were randomized to decorin 4 mg/kg or saline by intraventricular injection on PN8 and PN13. At PN21, the ventricular area was measured on coronal brain sections. Negative geotaxis was tested at PN14 in controls and in the decorin study group.. Ventricular size was not different between animals receiving either drug or water/saline. Intraventricular blood impaired neuromotor performance, but decorin had no effect.. Two drugs that block TGFβ by different mechanisms do not reduce ventricular dilatation in this model. Together with our previous work on losartan and pirfenidone, we conclude that blocking TGFβ alone does not prevent the development of PHVD.

Topics: Animals; Animals, Newborn; Brain; Cerebral Hemorrhage; Cerebral Ventricles; Colchicine; Decorin; Dilatation, Pathologic; Disease Models, Animal; Gravity Sensing; Injections, Intraventricular; Longevity; Motor Activity; Random Allocation; Rats; Rats, Wistar; Reflex, Righting; Transforming Growth Factor beta

Posthaemorrhagic ventricular dilatation (PHVD) after intraventricular haemorrhage (IVH) remains a significant problem in preterm infants. No treatment has reduced the need for cerebrospinal fluid (CSF) diversion. Considerable evidence implicates transforming growth factor-beta (TGF-beta) in the pathogenesis of PHVD. Pirfenidone and losartan reduce TGF-beta expression and decrease postinflammatory fibrosis in the lungs, kidneys, heart and liver. They have excellent CSF and brain penetration. We hypothesized that administration of pirfenidone or losartan would reduce ventricular dilatation.. Ninety-two rat pups underwent intraventricular blood injection on postnatal days (PN) 7 and 8, and were randomised to pirfenidone, losartan or water by gavage for 14 days. Neuromotor testing was carried out twice weekly. After sacrifice at PN21, ventricular area was measured on coronal sections using image-analysis software.. Ninety-five percent of animals undergoing IVH developed PHVD. Ventricular size was not significantly different between animals receiving either drug or water. Neuromotor testing at PN14 was significantly worse in IVH animals than in controls; neither drug improved performance in IVH animals.. Drugs that block TGF-beta do not reduce ventricular dilatation in this model. Further study is required to identify other cytokine targets and to determine how PHVD differs from postinflammatory fibrosis in other organs.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Cerebral Hemorrhage; Cerebral Ventricles; Dilatation, Pathologic; Disease Models, Animal; Losartan; Pyridones; Random Allocation; Rats; Rats, Wistar; Transforming Growth Factor beta

Mutations in the genes encoding transforming growth factor-beta receptor types I and II (TGFBR1 and TGFBR2, respectively) are commonly identified in patients with Loeys-Dietz syndrome, as well as some patients with Marfan's syndrome or familial thoracic aortic aneurysms and dissections. This suggests that there is considerable phenotypic heterogeneity associated with mutations in these genes. Because bicuspid aortic valve (BAV) is a congenital heart defect in patients with Loeys-Dietz syndrome, this study was conducted to investigate whether variants in TGFBR1 or TGFBR2 are responsible for sporadic BAV. Analysis of these genes in 35 patients with BAVs identified only known single-nucleotide polymorphisms or novel synonymous or intronic substitutions. In conclusion, mutations in TGFBR1 and TGFBR2 rarely cause sporadic BAV.

Topics: Adolescent; Adult; Aorta, Thoracic; Aortic Valve; Child; Child, Preschool; Dilatation, Pathologic; DNA; Female; Heart Defects, Congenital; Humans; Infant; Male; Mutation; Polymerase Chain Reaction; Prognosis; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta)/Smad's signalling pathway plays a pivotal role in organogenesis, oncogenesis, inflammation, repair and fibrosis. The aim of this study was to evaluate the morphology of muscle layers and the density and distribution of interstitial cells of Cajal (ICC) in the colon of Smad3 knockout mice.. Eighteen Smad3 wild-type mice and 12 null mice were sacrificed at age 4 months and the colons were collected for histology (Haematoxilin-Eosin, Masson thrichrome and Gomori silver staining), morphometry and immunohistochemistry (IHC) analysis. For IHC we used the c-Kit, alpha-smooth muscle actine (alpha-SMA), vimentin, desmin and neuronal cocktail (S-100, NSE, neurofilament 200) antibodies.. When sacrificed, 40% of the null mice showed different degrees of colon dilatation when compared with the wild-type. Histological and morphometric evaluation revealed a significant reduction in muscle layer thickness of the colon in all the null mice when compared with the wild-type. Immunohistochemistry evaluation showed a marked reduction, or even absence, of c-Kit immunoreactivity, which identifies ICC, in the colon of all the null mice, compared with the wild-type.. Smad3 null mice showed a marked reduction, or even absence, of ICC in the colon together with a concomitant reduction of intestinal smooth muscle layer thickness. This data could account for the colonic dilation observed in approximately 40% of the Smad3 null mice. Alteration of intestinal smooth muscle layers and ICC could also be involved in the resistance of the Smad3 null mice to develop colonic fibrosis.

Topics: Animals; Coiled Bodies; Colon; Dilatation, Pathologic; Immunoenzyme Techniques; Mice; Mice, Knockout; Muscle Proteins; Muscle, Smooth; Phenotype; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Light microscopy study of the lumbar spinal meninges of a murine model of Marfan syndrome.. Characterize the pathology of the lumbosacral meninges in Marfan syndrome, seeking clues to the pathophysiology behind dural ectasia.. Dural ectasia is common in Marfan syndrome. The etiology of dural ectasia is unknown, but is conjectured to be related to constitutionally weak spinal dura. The morphology of the lumbar dura in Marfan syndrome has not been described, as it has in other tissues affected by Marfan syndrome.. The lumbosacral dura were removed from three 4-month-old mice, 1 homozygote (mgR/mgR) expressing the murine Marfan phenotype, 1 heterozygote expressing wild-type phenotype, and 1 homozygote wildtype. Hematoxylin and eosin, elastochrome, and immunohistochemical stains against activated transforming growth factor beta, gelatinase A (matrix metalloproteinase-2), and gelatinase-B (matrix metalloproteinase-9) were used for light microscopic evaluation.. No difference was noted between the heterozygous and wild-type mice in dural connective tissue morphology. The homozygote (mgR/mgR) had a marked attenuation of the dura overall, in addition to elastic fiber disorganization. The homozygote dura also stained for increased presence of activated transforming growth factor beta and matrix metalloproteinase-2, but not matrix metalloproteinase-9.. These morphologic findings in the Marfan phenotype mouse mimic the findings of disordered elastic-fibers in other Marfan tissues and demonstrate gross attenuation of the tissue architecture, corroborating the theory that dural ectasia in Marfan syndrome results from hydrostatic pressure on weakened dura. These changes may be due in part to transforming growth factor beta overactivation and gelatinase-A-mediated elastolysis and collagen breakdown.

Topics: Animals; Biomarkers; Cauda Equina; Dilatation, Pathologic; Disease Models, Animal; Dura Mater; Fibrillins; Lumbosacral Region; Marfan Syndrome; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Microfilament Proteins; Transforming Growth Factor beta

Post haemorrhagic ventricular dilatation is associated with a high rate of disability, multiple impairments and adverse effects of shunt surgery for hydrocephalus. Post haemorrhagic ventricular dilatation results initially from multiple small blood clots throughout the cerebrospinal fluid channels impeding circulation and re-absorption. Transforming growth factor beta is released into the cerebrospinal fluid and there is evidence that this cytokine stimulates the laying down of extracellular matrix proteins which produce permanent obstruction to the cerebrospinal fluid pathways. Prolonged raised pressure, pro-inflammatory cytokines and free radical damage from iron may contribute to periventricular white matter damage and subsequent disability. Interventions such as early lumbar punctures, diuretic drugs to reduce cerebrospinal fluid production and intraventricular fibrinolytic therapy have been tested and, not only fail to prevent shunt dependence, death or disability, but have significant adverse effects. Surgical interventions such as subcutaneous reservoir, external drain, choroid plexus coagulation and third ventriculostomy have not been subject to controlled trial. Ventriculoperitoneal shunt is not feasible in the early phase after intraventricular haemorrhage but, despite the problems with blockages and infections, remains the only option for infants with excessive head expansion over periods of weeks. We have piloted drainage, irrigation and fibrinolytic therapy as a way of removing blood early enough to stop the progressive deposition of matrix proteins, permanent hydrocephalus and shunt dependence.

Topics: Cerebral Hemorrhage; Cerebral Ventricles; Cytokines; Dilatation, Pathologic; Drainage; Humans; Hydrocephalus; Infant, Newborn; Pilot Projects; Therapeutic Irrigation; Transforming Growth Factor beta; Transforming Growth Factor beta1

To describe histopathological and immunohistochemical findings in human corneas after myopic laser in situ keratomileusis (LASIK) followed by iatrogenic keratectasia and after hyperopic LASIK.. Department of Ophthalmology, University of Innsbruck, Innsbruck, Austria.. Clinical, histological, and immunohistochemical investigations were performed of 1 human cornea with iatrogenic keratectasia following myopic LASIK and 1 human cornea with irregular astigmatism and central scar formation after hyperopic LASIK. Corneal buttons were obtained during penetrating keratoplasty in both patients.. Histopathological examination showed thinning of the central stroma with a posterior residual thickness of 190 microm in the patient with iatrogenic keratectasia after myopic LASIK and significant midperipheral thinning in the patient who had hyperopic LASIK. However, this characteristic ablation profile of the stroma after hyperopic LASIK was partially mitigated and compensated by the epithelium, which was significantly thinned in the center and markedly thickened in the midperiphery. Traces of wound healing with minimal scar tissue were present at the flap margin after myopic and hyperopic LASIK. In a few sections of the cornea with keratectasia after myopia LASIK, only a few collagen lamellae were visible crossing between the posterior residual stroma and the superficial flap. Immunohistochemical examination revealed minimally increased staining of dermatan sulfate proteoglycan within the stroma adjacent to the interface of the microkeratome incision. Increased staining of hepatocyte growth factor was found on keratocytes/fibroblasts at the flap margin in both corneas.. The wound-healing response is generally poor after LASIK, which may result in significant weakening of the tensile strength of the cornea after myopic LASIK, probably due to biomechanically ineffective superficial lamella. After LASIK in patients with high hyperopia, compensatory epithelial thickening in the annular midperipheral ablation zone might be partly responsible for regression.

Topics: Adult; Chondroitin Sulfate Proteoglycans; Collagen; Cornea; Corneal Diseases; Dermatan Sulfate; Dilatation, Pathologic; Female; Hepatocyte Growth Factor; Humans; Hyperopia; Iatrogenic Disease; Immunoenzyme Techniques; Keratan Sulfate; Keratomileusis, Laser In Situ; Keratoplasty, Penetrating; Male; Middle Aged; Myopia; Platelet-Derived Growth Factor; Transforming Growth Factor beta

To examine the maturational-delay hypothesis of primary megaureter (PM), i.e. that the condition arises by a segmental maturational delay of the ureteric wall that can resolve spontaneously within the first year of life, using comparative immunocytochemistry of ureters resected from infants and from homologous pre-natal ureters.. Seventeen distal urinary tracts were obtained from children with PM who were referred for surgery (aged 6 months to 8 years, mean 2.1 years). These were compared with ureteric buds obtained from 11-week-old human and 11- to 38-week-old calf fetuses. The samples were immunostained using a monoclonal antibody specific for transforming growth factor beta (TGF-beta).. The histological appearances of the narrowed ureteric segments from patients under 18 months old were like the fetal ureteric buds at 26-38 weeks of gestation. Positive TGF-beta immunoreactions were detected in the longitudinal muscle layer in the ureter from patients 6-12 months old. Such reactions weakened progressively in those patients older than 1 year, becoming negative in all children older than 3 years. The TGF-beta immunolabelling in resected ureters was closely similar to that in fetal ureters from 20 to 26-week old calves.. From these results, PM should be ascribed to a segmental developmental delay of the terminal ureter arising at about 20 weeks of gestation, with a possible pathogenetic involvement of autocrine TGF-beta overexpression.

Topics: Animals; Cattle; Child; Child, Preschool; Dilatation, Pathologic; Humans; Immunohistochemistry; Infant; Transforming Growth Factor beta; Up-Regulation; Ureteral Diseases

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional polypeptide that controls the production of extracellular matrix protein. Platelets store a large quantity of TGF-beta 1, which is released at hemorrhage. We recently reported that human recombinant TGF-beta 1 induced communicating hydrocephalus in mice. The aim of this study was to determine whether TGF-beta 1 is related to the development of communicating hydrocephalus after subarachnoid hemorrhage (SAH).. TGF-beta 1 in the cerebrospinal fluid of 24 patients with SAH was measured with enzyme-linked immunosorbent assay. The levels were compared between hydrocephalic and nonhydrocephalic groups. Western blot analysis was performed to determine active TGF-beta 1 in the cerebrospinal fluid.. TGF-beta 1 rapidly decreased from the onset of SAH. The level of TGF-beta 1 of 13 patients showing ventricular dilatation with periventricular low density on computed tomographic scan was 1.07 +/- 0.37 ng/mL on days 12 through 14, which was significantly higher than 0.52 +/- 0.21 ng/mL in patients without ventricular dilatation (P < .02). Furthermore, the TGF-beta 1 level of patients who had undergone ventriculoperitoneal shunt (n = 11) was 1.11 +/- 0.09 ng/mL on days 12 through 14, which was also higher than the level of the nonshunt group (n = 13) (0.56 +/- 0.22 ng/mL; P < .01). A 25-kD band was demonstrated by Western blot analysis in the cerebrospinal fluid of a patient with SAH.. Our results strongly suggest that TGF-beta 1 plays an important role in generating communicating hydrocephalus after SAH.

Topics: Adult; Aged; Cerebral Ventricles; Dilatation, Pathologic; Female; Humans; Hydrocephalus; Male; Middle Aged; Subarachnoid Hemorrhage; Transforming Growth Factor beta