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Functional differences in human aortic valve interstitial cells from patients with varying calcific aortic valve disease

Calcific aortic valve disease (CAVD) is characterized by progressive stiffening of aortic valve (AV) tissues, inducing stenosis and insufficiency. Bicuspid aortic valve (BAV) is a common congenital defect in which the AV has two leaflets rather than three, with BAV patients developing CAVD decades y...

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Autores principales: Tuscher, Robin, Khang, Alex, West, Toni M., Camillo, Chiara, Ferrari, Giovanni, Sacks, Michael S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10316512/
https://www.ncbi.nlm.nih.gov/pubmed/37405132
http://dx.doi.org/10.3389/fphys.2023.1168691
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author Tuscher, Robin
Khang, Alex
West, Toni M.
Camillo, Chiara
Ferrari, Giovanni
Sacks, Michael S.
author_facet Tuscher, Robin
Khang, Alex
West, Toni M.
Camillo, Chiara
Ferrari, Giovanni
Sacks, Michael S.
author_sort Tuscher, Robin
collection PubMed
description Calcific aortic valve disease (CAVD) is characterized by progressive stiffening of aortic valve (AV) tissues, inducing stenosis and insufficiency. Bicuspid aortic valve (BAV) is a common congenital defect in which the AV has two leaflets rather than three, with BAV patients developing CAVD decades years earlier than in the general population. Current treatment for CAVD remains surgical replacement with its continued durability problems, as there are no pharmaceutical therapies or other alternative treatments available. Before such therapeutic approaches can be developed, a deeper understanding of CAVD disease mechanisms is clearly required. It is known that AV interstitial cells (AVICs) maintain the AV extracellular matrix and are typically quiescent in the normal state, transitioning into an activated, myofibroblast-like state during periods of growth or disease. One proposed mechanism of CAVD is the subsequent transition of AVICs into an osteoblast-like phenotype. A sensitive indicator of AVIC phenotypic state is enhanced basal contractility (tonus), so that AVICs from diseased AV will exhibit a higher basal tonus level. The goals of the present study were thus to assess the hypothesis that different human CAVD states lead to different biophysical AVIC states. To accomplish this, we characterized AVIC basal tonus behaviors from diseased human AV tissues embedded in 3D hydrogels. Established methods were utilized to track AVIC-induced gel displacements and shape changes after the application of Cytochalasin D (an actin polymerization inhibitor) to depolymerize the AVIC stress fibers. Results indicated that human diseased AVICs from the non-calcified region of TAVs were significantly more activated than AVICs from the corresponding calcified region. In addition, AVICs from the raphe region of BAVs were more activated than from the non-raphe region. Interestingly, we observed significantly greater basal tonus levels in females compared to males. Furthermore, the overall AVIC shape changes after Cytochalasin suggested that AVICs from TAVs and BAVs develop different stress fiber architectures. These findings are the first evidence of sex-specific differences in basal tonus state in human AVICs in varying disease states. Future studies are underway to quantify stress fiber mechanical behaviors to further elucidate CAVD disease mechanisms.
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spelling pubmed-103165122023-07-04 Functional differences in human aortic valve interstitial cells from patients with varying calcific aortic valve disease Tuscher, Robin Khang, Alex West, Toni M. Camillo, Chiara Ferrari, Giovanni Sacks, Michael S. Front Physiol Physiology Calcific aortic valve disease (CAVD) is characterized by progressive stiffening of aortic valve (AV) tissues, inducing stenosis and insufficiency. Bicuspid aortic valve (BAV) is a common congenital defect in which the AV has two leaflets rather than three, with BAV patients developing CAVD decades years earlier than in the general population. Current treatment for CAVD remains surgical replacement with its continued durability problems, as there are no pharmaceutical therapies or other alternative treatments available. Before such therapeutic approaches can be developed, a deeper understanding of CAVD disease mechanisms is clearly required. It is known that AV interstitial cells (AVICs) maintain the AV extracellular matrix and are typically quiescent in the normal state, transitioning into an activated, myofibroblast-like state during periods of growth or disease. One proposed mechanism of CAVD is the subsequent transition of AVICs into an osteoblast-like phenotype. A sensitive indicator of AVIC phenotypic state is enhanced basal contractility (tonus), so that AVICs from diseased AV will exhibit a higher basal tonus level. The goals of the present study were thus to assess the hypothesis that different human CAVD states lead to different biophysical AVIC states. To accomplish this, we characterized AVIC basal tonus behaviors from diseased human AV tissues embedded in 3D hydrogels. Established methods were utilized to track AVIC-induced gel displacements and shape changes after the application of Cytochalasin D (an actin polymerization inhibitor) to depolymerize the AVIC stress fibers. Results indicated that human diseased AVICs from the non-calcified region of TAVs were significantly more activated than AVICs from the corresponding calcified region. In addition, AVICs from the raphe region of BAVs were more activated than from the non-raphe region. Interestingly, we observed significantly greater basal tonus levels in females compared to males. Furthermore, the overall AVIC shape changes after Cytochalasin suggested that AVICs from TAVs and BAVs develop different stress fiber architectures. These findings are the first evidence of sex-specific differences in basal tonus state in human AVICs in varying disease states. Future studies are underway to quantify stress fiber mechanical behaviors to further elucidate CAVD disease mechanisms. Frontiers Media S.A. 2023-06-19 /pmc/articles/PMC10316512/ /pubmed/37405132 http://dx.doi.org/10.3389/fphys.2023.1168691 Text en Copyright © 2023 Tuscher, Khang, West, Camillo, Ferrari and Sacks. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Tuscher, Robin
Khang, Alex
West, Toni M.
Camillo, Chiara
Ferrari, Giovanni
Sacks, Michael S.
Functional differences in human aortic valve interstitial cells from patients with varying calcific aortic valve disease
title Functional differences in human aortic valve interstitial cells from patients with varying calcific aortic valve disease
title_full Functional differences in human aortic valve interstitial cells from patients with varying calcific aortic valve disease
title_fullStr Functional differences in human aortic valve interstitial cells from patients with varying calcific aortic valve disease
title_full_unstemmed Functional differences in human aortic valve interstitial cells from patients with varying calcific aortic valve disease
title_short Functional differences in human aortic valve interstitial cells from patients with varying calcific aortic valve disease
title_sort functional differences in human aortic valve interstitial cells from patients with varying calcific aortic valve disease
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10316512/
https://www.ncbi.nlm.nih.gov/pubmed/37405132
http://dx.doi.org/10.3389/fphys.2023.1168691
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