Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve
Abstract Disturbed flow has been suggested to contribute to aneurysm susceptibility in bicuspid aortic valve (BAV) patients. Lately, flow has emerged as an important modulator of DNA methylation. Hear we combined global methylation analysis with in vitro studies of flow-sensitive methylation to iden...
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Nature Portfolio
2018
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oai:doaj.org-article:73c1b1498f5e4c11a43e09c43ee43b982021-12-02T15:09:04ZAltered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve10.1038/s41598-018-20642-42045-2322https://doaj.org/article/73c1b1498f5e4c11a43e09c43ee43b982018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-20642-4https://doaj.org/toc/2045-2322Abstract Disturbed flow has been suggested to contribute to aneurysm susceptibility in bicuspid aortic valve (BAV) patients. Lately, flow has emerged as an important modulator of DNA methylation. Hear we combined global methylation analysis with in vitro studies of flow-sensitive methylation to identify biological processes associated with BAV-aortopathy and the potential contribution of flow. Biopsies from non-dilated and dilated ascending aortas were collected from BAV (n = 21) and tricuspid aortic valve (TAV) patients (n = 23). DNA methylation and gene expression was measured in aortic intima-media tissue samples, and in EA.hy926 and primary aortic endothelial cells (ECs) isolated from BAV and TAV exposed to oscillatory (±12 dynes/cm2) or laminar (12 dynes/cm2) flow. We show methylation changes related to epithelial-mesenchymal-transition (EMT) in the non-dilated BAV aorta, associated with oscillatory flow related to endocytosis. The results indicate that the flow-response in BAV ECs involves hypomethylation and increased expression of WNT/β-catenin genes, as opposed to an angiogenic profile in TAV ECs. The EMT-signature was exasperated in dilated BAV aortas. Aberrant EMT in BAV aortic walls could contribute to increased aneurysm susceptibility, and may be due to disturbed flow-exposure. Perturbations during the spatiotemporally related embryonic development of ascending aorta and semilunar valves can however not be excluded.Hanna M. BjörckLei DuSilvia PulignaniValentina PaloschiKarin LundströmerAlexandra S. KostinaCecilia ÖsterholmAnna MalashichevaAnna KostarevaArturo EvangelistaGisela Teixidó-TuraShohreh MalekiAnders Franco-CerecedaPer ErikssonMechanistic Interrogation of Bicuspid Aortic Valve associated Aortopathy (MIBAVA) Leducq ConsortiumNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-15 (2018) |
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Medicine R Science Q Hanna M. Björck Lei Du Silvia Pulignani Valentina Paloschi Karin Lundströmer Alexandra S. Kostina Cecilia Österholm Anna Malashicheva Anna Kostareva Arturo Evangelista Gisela Teixidó-Tura Shohreh Maleki Anders Franco-Cereceda Per Eriksson Mechanistic Interrogation of Bicuspid Aortic Valve associated Aortopathy (MIBAVA) Leducq Consortium Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve |
| description |
Abstract Disturbed flow has been suggested to contribute to aneurysm susceptibility in bicuspid aortic valve (BAV) patients. Lately, flow has emerged as an important modulator of DNA methylation. Hear we combined global methylation analysis with in vitro studies of flow-sensitive methylation to identify biological processes associated with BAV-aortopathy and the potential contribution of flow. Biopsies from non-dilated and dilated ascending aortas were collected from BAV (n = 21) and tricuspid aortic valve (TAV) patients (n = 23). DNA methylation and gene expression was measured in aortic intima-media tissue samples, and in EA.hy926 and primary aortic endothelial cells (ECs) isolated from BAV and TAV exposed to oscillatory (±12 dynes/cm2) or laminar (12 dynes/cm2) flow. We show methylation changes related to epithelial-mesenchymal-transition (EMT) in the non-dilated BAV aorta, associated with oscillatory flow related to endocytosis. The results indicate that the flow-response in BAV ECs involves hypomethylation and increased expression of WNT/β-catenin genes, as opposed to an angiogenic profile in TAV ECs. The EMT-signature was exasperated in dilated BAV aortas. Aberrant EMT in BAV aortic walls could contribute to increased aneurysm susceptibility, and may be due to disturbed flow-exposure. Perturbations during the spatiotemporally related embryonic development of ascending aorta and semilunar valves can however not be excluded. |
| format |
article |
| author |
Hanna M. Björck Lei Du Silvia Pulignani Valentina Paloschi Karin Lundströmer Alexandra S. Kostina Cecilia Österholm Anna Malashicheva Anna Kostareva Arturo Evangelista Gisela Teixidó-Tura Shohreh Maleki Anders Franco-Cereceda Per Eriksson Mechanistic Interrogation of Bicuspid Aortic Valve associated Aortopathy (MIBAVA) Leducq Consortium |
| author_facet |
Hanna M. Björck Lei Du Silvia Pulignani Valentina Paloschi Karin Lundströmer Alexandra S. Kostina Cecilia Österholm Anna Malashicheva Anna Kostareva Arturo Evangelista Gisela Teixidó-Tura Shohreh Maleki Anders Franco-Cereceda Per Eriksson Mechanistic Interrogation of Bicuspid Aortic Valve associated Aortopathy (MIBAVA) Leducq Consortium |
| author_sort |
Hanna M. Björck |
| title |
Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve |
| title_short |
Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve |
| title_full |
Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve |
| title_fullStr |
Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve |
| title_full_unstemmed |
Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve |
| title_sort |
altered dna methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve |
| publisher |
Nature Portfolio |
| publishDate |
2018 |
| url |
https://doaj.org/article/73c1b1498f5e4c11a43e09c43ee43b98 |
| work_keys_str_mv |
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