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• W56193015 abstract "The Smooth Muscle Cell (SMC) Phenotype is characterized by important plasticity and it plays crucial functional role in physiological and pathological conditions. Modulation of SMC Phenotype in arteries is a key etiological feature of some major human pathologies, including atherosclerosis, hypertension and vessel restenosis. Expression of SMCs marker-genes is also important in chronic diseases of other organs, such as in kidney or hepatic fibrosis and in cancer metastasis. So, study of the molecular mechanisms which affect SMC phenotype is necessary in order to develop new therapeutic approaches to combat to these diseases.Function of many tissues such as the vasculature is regulated by the sympathetic nervous system. The aim of this study was first, to examine in vitro whether the stimulation of alpha (α) and beta (β) adrenergic receptors (ARs) can control the expression of SMCs marker-genes in vitro and in case it did, to probe the molecular mechanisms via which α1-ARs (subtypes α1A and α1B) and β-ARs affect and regulate SMC Phenotype. Secondly, we wanted to investigate if the exogenous expression of Myocardin can cause Epithelial to Mesenchymal Transition (EΜΤ)-like changes in endothelial cells in vitro.For our experiments, we used two different cell populations : a) A7r5, which are differentiated Smooth Muscle Cells isolated from rat embryonic aorta, and b) ΝΙΗ3Τ3, mouse fibroblasts, in order to examine how stimulation of ARs modulates the expression of these marker-genes in differentiated SMCs (A7r5) and in mesenchymal cells which can convert to SMCs (ΝΙΗ3Τ3), respectively.As a marker for the expression of SMC Phenotype, we monitored the expression of cytoskeletal, structural protein-markers, such as Smooth Muscle-α-Actin (SM-α-Actin), SM-Myosin Heavy Chain (SM-MHC), h1-Calponin (SM-Calponin) and SM22α (transgelin) at two levels: a) using specific antibodies or b) using reporter plasmids in which the minimal promoters of the above genes drive luciferase gene transcription and hence activity. The coordinate transcriptional activation of these genes is, in major part, regulated by the function of CArG boxes in their promoters, which bind Serum Response Factor (SRF). In SMCs, SRF mediates its transcriptional effects via essential complex formation with members of the Myocardin family, which includes Myocardin (Myocd), Myocardin-Related Transcription Factor-A (MRTF-A) and MRTF-B.In our study, we initially noticed that these two cell populations do not express α1-ARs (subtypes α1Α and α1Β) endogenously, but when we transfect them with the plasmids expressing α1Α and α1Β ARs, the cells respond to α1-ARs agonist stimulation. In addition, we discovered that A7r5 cells express endogenous β-ARs. From our experiments, we concluded that these receptors can modulate SMC Phenotype in distinct way. This depends on both the specific subtype of receptor as well as on the cellular background (cell type).More specific, we observed that in A7r5 cells:a) activation of α1A-ARs by phenylephrine induces the expression of all four marker-genes at a transcriptional and at a protein level, b) activation of the SM22α minimal promoter by α1A-ARs depends on CΑrG boxes, while activation of the SM-Calponin minimal promoter does not depend on the presence of CΑrG boxes, c) activation of α1B-ARs induces the transcriptional activity of the minimal promoters of SM22α and SM-Calponin but does not affect the transcriptional activity of the minimal promoter of SM-α-Αctin and SM-MHC, d) activation of both the SM22α and the SM-Calponin minimal promoters by α1B-ARs depends on the presence of CΑrG boxes, e) on the contrary, β-ARs affect the transcription of SMCs marker-genes in an opposite way to α1-ARs reducing the transcriptional activity of the minimal promoters of SM-Calponin, SM-α-Αctin and SM-MHC genes, without affecting the transcriptional activity of the SM22α promoter.Additionally, we noticed that in ΝΙΗ3Τ3 cells:a) α1Α-ARs induce transcriptional activity of minimal promoters of SMC marker-genes, b) activation of minimal promoters of SM22α and SM-Calponin by α1A-ARs does not depend on CΑrG boxes, c) activation of α1B-ARs induce the transcriptional activity of the minimal promoters of SM22α, SM-Calponin και SM-MHC but does not affect the transcriptional activity of the minimal promoter of SM-α-Αctin.Based on the above findings, we conclude that: 1) Stimulation of α1-ARs drives an increased expression of SMC marker genes and consequently α1-ARs function, at least in vitro, as factors which have the ability to induce/maintain the SMC Phenotype.2) The activity of α1-ARs depends variably on the presence of CArG boxes (SREs) and differs between these minimal promoters. In essence, different promoters use their CArG boxes in a different way. This is in support of the hypothesis that combinational use of transcriptional factors is essential for «plastic» expression of the SMC Phenotype.3) The two subtypes of α1-ARs examined, α1Α and α1Β, display obvious differences in stimulating SM-specific gene expression and consequently these subtypes may play different functional role in vessels and in other tissues in which they are expressed. 4) On the contrary, β-ARs inhibit the expression of SMC marker-genes. Therefore, the final result of vascular sympathetic stimulation would depend on the combined action of α και β ARs. This action will differ in different vessels, depending on the relative expression of these receptors and their subtypes. In addition, adenoviral expression of Myocardin in human umbilical vein endothelial Cells (HUVECs) induced phenotypic alterations, evidenced by morphological changes and by de novo expression of SM-α-Αctin and SM-Calponin at the protein level. These observations are compatible with an Epithelial to Mesenchymal Transition (EMT), a process which plays an important role in embryogenesis, tissue and organs formation and angiogenesis, but also participates, in fibrosis and cancer metastasis. Consequently, vascular endothelial cells can undergo in EMT and may contribute in cellular differentiation and in tissue formation. We conclude that the expression of Myocardin is sufficient to cause EMT-like changes in human endothelial cells. This may lead to cellular trans-differentiation and contribution of these cells in active tissue remodeling such as in atherosclerosis and in cardiac failure." @default.
• W56193015 created "2016-06-24" @default.
• W56193015 creator A5089619271 @default.
• W56193015 date "2012-04-24" @default.
• W56193015 modified "2023-09-27" @default.
• W56193015 title "Μοριακός έλεγχος τού λείου μυϊκού φαινότυπου" @default.
• W56193015 hasPublicationYear "2012" @default.
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