scholarly journals Phenotypic and Functional Changes of Endothelial and Smooth Muscle Cells in Thoracic Aortic Aneurysms

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Anna Malashicheva ◽  
Daria Kostina ◽  
Aleksandra Kostina ◽  
Olga Irtyuga ◽  
Irina Voronkina ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Aortic Valve ◽  
Smooth Muscle Cells ◽  
Aortic Wall ◽  
Muscle Cells ◽  
Aortic Aneurysms ◽  
Cell Phenotype ◽  
Functional Markers ◽  
Thoracic Aortic Aneurysms

Thoracic aortic aneurysm develops as a result of complex series of events that alter the cellular structure and the composition of the extracellular matrix of the aortic wall. The purpose of the present work was to study the cellular functions of endothelial and smooth muscle cells from the patients with aneurysms of the thoracic aorta. We studied endothelial and smooth muscle cells from aneurysms in patients with bicuspid aortic valve and with tricuspid aortic valve. The expression of key markers of endothelial (CD31, vWF, and VE-cadherin) and smooth muscle (SMA, SM22α, calponin, and vimentin) cells as well extracellular matrix and MMP activity was studied as well as and apoptosis and cell proliferation. Expression of functional markers of endothelial and smooth muscle cells was reduced in patient cells. Cellular proliferation, migration, and synthesis of extracellular matrix proteins are attenuated in the cells of the patients. We show for the first time that aortic endothelial cell phenotype is changed in the thoracic aortic aneurysms compared to normal aortic wall. In conclusion both endothelial and smooth muscle cells from aneurysms of the ascending aorta have downregulated specific cellular markers and altered functional properties, such as growth rate, apoptosis induction, and extracellular matrix synthesis.

Abstract 496: Extracellular Matrix Secretion by Vascular Smooth Muscle Cells: Role of MiR-195 and MiR-29b

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Anna Zampetaki ◽  
Xiaoke Yin ◽  
Ursula Mayr ◽  
Renata Gomes ◽  
Sarah Langley ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Abdominal Aortic ◽  
Vascular Smcs

Rationale: Extracellular matrix (ECM) remodeling is a key function of vascular smooth muscle cells (SMCs). MicroRNAs (miRNAs), in particular the miR-29 family and miR-195, have been implicated in the control of ECM secretion. Objective: To perform a proteomics comparison of miRNA effects on ECM production by vascular SMCs. Methods and Results: Murine SMCs were transfected with miRNA mimics and antimiRs of miR-29b and miR-195, and their conditioned medium was analyzed by mass spectrometry. Both miRNAs targeted a cadre of ECM proteins, including proteoglycans, collagens, proteases, elastin and proteins associated with elastic microfibrils, albeit miR-29 showed a stronger effect. The proteomics findings were subsequently validated at the transcription level using quantitative polymerase chain reaction. Similar to miR-29, in vivo inhibition of miR-195 by intraperitoneal injection of cholesterol bound antagomiRs led to significant alterations of elastin expression in murine aortas. Since elastin degradation is a key event in aortic aneurysm formation, we investigated miR-195 expression in patients. In human aortic aneurysmal tissue, miR-195 expression was reduced compared to non-aneurysmal tissue. In plasma, a comparison between male patients with abdominal aortic aneurysms and controls matched for diabetes and hypertension returned a panel of five highly correlated miRNAs: miR-195, miR-125b, miR-148a, miR-20a and miR-340 showed significant inverse associations with the presence of abdominal aortic aneurysms and aortic diameter, with miR-195 dominating in terms of association strength. Conclusions: Using proteomic analysis, we compared the effect of miR-29 and miR-195 on ECM secretion by vascular SMCs and identified novel miRNA targets. Findings in patients support an important role for miR-195 in vascular remodeling as evidenced by reduced miR-195 expression in human aneurysmal tissue and an inverse correlation between plasma miR-195 levels and aortic diameter.

scholarly journals A preliminary proteomic evaluation of smooth muscle cells in thoracic aortic aneurysms

2014 ◽  
Vol 38 ◽  
pp. 238-252
Author(s):  
Ceyda AÇILAN AYHAN ◽  
Betül BAYKAL ◽  
Müge SERHATLI ◽  
Ömer KAÇAR ◽  
Zelal ADIGÜZEL ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Aortic Aneurysms ◽  
Thoracic Aortic Aneurysms

scholarly journals Studies on sporadic non-syndromic thoracic aortic aneurysms: 1. Deregulation of Jagged/Notch 1 homeostasis and selection of synthetic/secretor phenotype smooth muscle cells

2018 ◽  
Vol 25 (1_suppl) ◽  
pp. 42-50 ◽  
Author(s):  
Anna Chiarini ◽  
Francesco Onorati ◽  
Maddalena Marconi ◽  
Alessandra Pasquali ◽  
Cristina Patuzzo ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Muscle Cells ◽  
Aortic Aneurysms ◽  
Aortic Smooth Muscle Cells ◽  
Thoracic Aortic Aneurysms ◽  
Aortic Smooth Muscle ◽  
And Migration ◽  
Media Layer

Background Sporadic non-syndromic thoracic aortic aneurysms (SNSTAAs) are less well understood than familial non-syndromic or syndromic ones. The study aimed at defining the peculiar morphologic and molecular changes occurring in the media layer of SNSTAAs. Design This study was based on a single centre design. Methods Media layer samples taken from seven carefully selected SNSTAAs and seven reference patients (controls) were investigated via quantitative polymerase chain reaction, proteomics-bioinformatics, immunoblotting, quantitative histology, and immunohistochemistry/immunofluorescence. Results In SNSTAAs media, aortic smooth muscle cells numbers were halved due to an apoptotic process coupled with a negligible cell proliferation. Cystathionine γ-lyase was diffusely up-regulated. Surviving aortic smooth muscle cells exhibited diverging phenotypes: in inner- and outer-media contractile cells prevailed, having higher contents of smooth-muscle-α-actin holoprotein (45-kDa) and of caspase-3-cleaved smooth-muscle-α-actin 25-kDa fragments; in mid-media, aortic smooth muscle cells exhibited a synthetic/secretor phenotype, down-regulating vimentin, but up-regulating glial fibrillary acidic protein, trans-Golgi network 46 protein, Jagged1 (172-kDa) holoprotein, and Jagged1’s receptor Notch1. Extracellular soluble Jagged1 (42-kDa) fragments accumulated. Conclusions In SNSTAAs, there is a relentless aortic smooth muscle cells attrition caused by the up-regulated cystathionine γ-lyase. In mid-media, synthetic/secretor aortic smooth muscle cells intensify Jagged1/NOTCH1 signalling in the attempt to counterbalance the weakened aortic wall, due to aortic smooth muscle cells net loss and mechanical stress. Synthetic/secretor aortic smooth muscle cells are apoptosis-prone, and the accruing thrombin-cleaved Jagged1 fragments counteract the otherwise useful effects of Jagged1/NOTCH1 signalling, thus hampering tissue homeostasis/remodelling, and aortic smooth muscle cells adhesion, differentiation, and migration.

Abstract 4275: TGFBR2 Mutations Reduce Expression of Contractile Proteins in Aortic Smooth Muscle Cells and Predispose Individuals to Thoracic Aortic Aneurysms and Dissections

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Sakiko Inamoto ◽  
Callie Kwartler ◽  
Andrea Lafont ◽  
Yao Yun Liang ◽  
Van Tran Fadulu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Matched Control ◽  
Muscle Cells ◽  
Contractile Proteins ◽  
Aortic Aneurysms ◽  
Gain Of Function ◽  
Age And Gender ◽  
Thoracic Aortic Aneurysms ◽  
And Gender

Mutations in the TGF-β receptor type II gene ( TGFBR2 ) cause thoracic aortic aneurysms and dissections (TAAD). Studies have suggested a gain of function effect for these mutations, leading to increased TGF-β signaling in the aortic media and resulting in vascular disease. We sought to characterize the phenotype of smooth muscle cells (SMCs) harboring heterozygous missense TGFBR2 mutations and our data suggest that instead of a gain of function, TGFBR2 mutations cause TAAD as a result of a loss of function resulting in defective SMC differentiation. Using primary aortic SMCs from patients harboring TGFBR2 mutations (n=4), we show a global decrease in expression of SMC contractile proteins ( ACTA2 , MYH11 , CNN1 , SMTN , TPM1 , TPM2 , p <0.001) by quantitative PCR analysis when these cells are compared with age and gender matched control SMCs (n=4), along with no change in the expression of cytoskeletal proteins. Consistent with the decreased expression of contractile proteins in the mutant cells, there was increased expression of S100A4, a marker of de-differentiated SMCs (p<0.001). Analysis of fixed and frozen aortas from patients with TGFBR2 mutations (n=3) confirmed decreased in vivo expression of SMC contractile proteins when compared to control aortas (n=3). In control SMCs, addition of TGF- β significantly increased the expression of the SMC contractile proteins but the TGFBR2 SMCs showed no significant increase in expression of these proteins with TGF-β stimulation. We found that fibroblasts explanted from patients with TGFBR2 mutations (n=8) consistently fail to transform into myofibroblasts as assessed by expression of SMC contractile proteins after TGF-β stimulation, when compared with age and gender matched control fibroblasts (n=8). Finally, introduction of TGFBR2 missense mutations into a mouse mesenchymal embryonic cell line that is used as a model of SMC differentiation (10T1/2 cells) disrupts the expression of contractile proteins in these cells when assessed post-differentiation. These data suggest that TGFBR2 mutations disrupt differentiation of SMCs and myofibroblasts. This is the first genetic defect identified to lead to defective SMC differentiation.

scholarly journals Smooth Muscle Cells Isolated from Thoracic Aortic Aneurysms Exhibit Increased Genomic Damage, but Similar Tendency for Apoptosis

2012 ◽  
Vol 31 (10) ◽  
pp. 1523-1534 ◽  
Author(s):  
Ceyda Acilan ◽  
Muge Serhatli ◽  
Omer Kacar ◽  
Zelal Adiguzel ◽  
Altug Tuncer ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Aortic Aneurysms ◽  
Thoracic Aortic Aneurysms ◽  
Similar Tendency ◽  
Genomic Damage

Abstract 397: Analysis of Cell Phenotype in Relation to TGFβ Treatment of Aortic Smooth Muscle Cells and Myofibroblasts Isolated from Aortas and Valves of Thoracic Aortic Aneurysm Patients with a Tricuspid or a Bicuspid Valve

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Valentina Paloschi ◽  
Lasse Folkersen ◽  
Sanela Kurtovic ◽  
Dick Wagsater ◽  
Anders Franco Cereceda ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Thoracic Aortic Aneurysm ◽  
Muscle Cells ◽  
Cell Types ◽  
Cell Phenotype ◽  
Matrix Remodeling ◽  
Exon Arrays

Background Thoracic aortic aneurysm (TAA) is a pathological widening of the aorta, due to degeneration of extracellular matrix (ECM) and loss of smooth muscle cells (SMCs). Bicuspid aortic valve (BAV) is a congenital disorder present in 1-2 % of the population which makes TAA associated with BAV a common complication. Previously we showed that aortas isolated from BAV and normal tricuspid aortic valve (TAV) patients are different both at gene and protein levels. Particularly, differences in the TGFβ pathway seem to be crucial players in aneurysm development, affecting matrix remodeling and wound healing. Since SMCs and myofibroblasts are the critical cells responsible for these activities, we evaluated different properties of the cells focusing on fibronectin (FN) and its spliced versions, a target gene of TGFβ. Interestingly, extra domain A of FN (EDA) was previously described for its roles in vascular morphogenesis, as well as in processes like migration and proliferation. Methods and results Biopsies from the thoracic aorta and Aortic valves were collected during Elective Aortic Valve Replacement Surgery. mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=46) and BAV (n=77). Expression of EDA was found increased only in dilated aortas from TAV patients but not in BAV patients. Primary SMCs were isolated with the explant outgrowth technique from aortas of BAV and TAV patients (n=15). Myofibroblasts were isolated by collagenase digestion from BAV and TAV valves (n=30). Cells were cultured and treated with TGFβ at a concentration of 20 ng/ml for 6h. TGFβ treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in SMCs from TAV patients but not in cells derived from BAV patients. We have not observed clear differences in SMC proliferation and migration. Myofibrolasts analysis is ongoing. Conclusions So far, our results suggest that despite a decreased EDA-fibronectin expression in BAV cells, the phenotype of SMCs isolated from BAV and TAV patients in culture does not differ. However, impaired TGFβ signaling that may result in the increased susceptibility of BAV patients to develop TAA could be due to effects on other cell types.

Dynamically-Loaded 3-D Model to Study the ECM Organization of Aortic Smooth Muscle Cells in Aneurysmal Patients With Bicuspid Aortic Valve

2011 ◽  
Author(s):  
Wei He ◽  
Julie Phillippi ◽  
Christopher E. Miller ◽  
David A. Vorp ◽  
Thomas G. Gleason
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Smooth Muscle Cells ◽  
Bicuspid Aortic Valve ◽  
Elective Surgery ◽  
Muscle Cells ◽  
The United States ◽  
Aortic Aneurysms ◽  
Aortic Replacement ◽  
Valvular Stenosis

Rupture of aortic aneurysms and dissections are the fifteenth leading cause of a death in the United States [1]. Over 40% of patients undergoing elective surgery for ascending aortic replacement due to thoracic aortic aneurysm (TAA) have a congenital defect in the aortic valve know as bicuspid aortic valve (BAV) [2]. BAV patients have uniformly larger diameter aortic roots and ascending aortas compared to age- and sex-matched controls [3] and abnormal elasticity even in the absence of valvular stenosis or aneurysm [4] and this greatly increases the risk of aortic dissection and sudden death [5]. The cause of TAA is uncertain, but recent studies suggest that oxidative stress may play a role in the pathogenesis of TAAs by degrading the extracellular matrix (ECM). We identified that BAV smooth muscle cells (SMCs) lack sufficient resistance to reactive oxygen species to maintain ECM homeostasis [6, 7].

scholarly journals Strong Signs for a Weak Wall in Tricuspid Aortic Valve Associated Aneurysms and a Role for Osteopontin in Bicuspid Aortic Valve Associated Aneurysms

2019 ◽  
Vol 20 (19) ◽  
pp. 4782 ◽  
Author(s):  
Christian Stern ◽  
Bernhard Scharinger ◽  
Adrian Tuerkcan ◽  
Clemens Nebert ◽  
Teresa Mimler ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Bicuspid Aortic Valve ◽  
Aortic Wall ◽  
Muscle Cells ◽  
Vascular Wall ◽  
Aortic Tissue

Central processes in the pathogenesis of TAV- (tricuspid aortic valve) and BAV- (bicuspid aortic valve) associated ascending thoracic aortic aneurysm (ATAA) development are still unknown. To gain new insights, we have collected aortic tissue and isolated smooth muscle cells of aneurysmal tissue and subjected them to in situ and in vitro analyses. We analyzed aortic tissue from 78 patients (31 controls, 28 TAV-ATAAs, and 19 BAV-ATAAs) and established 30 primary smooth muscle cell cultures. Analyses included histochemistry, immuno-, auto-fluorescence-based image analyses, and cellular analyses including smooth muscle cell contraction studies. With regard to TAV associated aneurysms, we observed a strong impairment of the vascular wall, which appears on different levels—structure and dimension of the layers (reduced media thickness, increased intima thickness, atherosclerotic changes, degeneration of aortic media, decrease of collagen, and increase of elastic fiber free area) as well as on the cellular level (accumulation of fibroblasts/myofibroblasts, and increase in the number of smooth muscle cells with a reduced alpha smooth muscle actin (α-SM actin) content per cell). The pathological changes in the aortic wall of BAV patients were much less pronounced—apart from an increased expression of osteopontin (OPN) in the vascular wall which stem from smooth muscle cells, we observed a trend towards increased calcification of the aortic wall (increase significantly associated with age). These observations provide strong evidence for different pathological processes and different disease mechanisms to occur in BAV- and TAV-associated aneurysms.

Endothelium in Aortic Aneurysm Disease: New Insights

2020 ◽  
Vol 27 (7) ◽  
pp. 1081-1088 ◽  
Author(s):  
Eleftherios Spartalis ◽  
Michael Spartalis ◽  
Antonios Athanasiou ◽  
Stavroula A. Paschou ◽  
Nikolaos Patelis ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Smooth Muscle ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Aortic Wall ◽  
Muscle Cells ◽  
Aortic Aneurysms

Inflammation is recognized as a fundamental element in the development and growth of aortic aneurysms. Aortic aneurysm is correlated with aortic wall deformities and injury, as a result of inflammation, matrix metalloproteinases activation, oxidative stress, and apoptosis of vascular smooth muscle cells. The endothelial wall has a critical part in the inflammation of the aorta and endothelial heterogeneity has proven to be significant for modeling aneurysm formation. Endothelial shear stress and blood flow affect the aortic wall through hindrance of cytokines and adhesion molecules excreted by endothelial cells, causing reduction of the inflammation process in the media and adventitia. This pathophysiological process results in the disruption of elastic fibers, degradation of collagen fibers, and destruction of vascular smooth muscle cells. Consequently, the aortic wall is impaired due to reduced thickness, decreased mechanical function, and cannot tolerate the impact of blood flow leading to aortic expansion. Surgery is still considered the mainstay therapy for large aortic aneurysms. The prevention of aortic dilation, though, is based on the hinderance of endothelial dysregulation with drugs, the reduction of reactive oxygen and nitrogen species, and also the reduction of pro-inflammatory molecules and metalloproteinases. Further investigations are required to enlighten the emerging role of endothelial cells in aortic disease.

Evaluation of apoptotic molecular pathways for smooth muscle cells isolated from thoracic aortic aneurysms in response to oxidized sterols

2014 ◽  
Vol 41 (12) ◽  
pp. 7875-7884 ◽  
Author(s):  
Zelal Adiguzel ◽  
Nazli Arda ◽  
Omer Kacar ◽  
Muge Serhatli ◽  
Serpil Gezer Tas ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Aortic Aneurysms ◽  
Molecular Pathways ◽  
Thoracic Aortic Aneurysms
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