TY - JOUR

T1 - Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve

AU - Mechanistic Interrogation

AU - Bjorck, Hanna M.

AU - Du, Lei

AU - Pulignani, Silvia

AU - Paloschi, Valentina

AU - Lundstromer, Karin

AU - Kostina, Alexandra S.

AU - Osterholm, Cecilia

AU - Malashicheva, Anna

AU - Kostareva, Anna

AU - Evangelista, Arturo

AU - Teixido-Tura, Gisela

AU - Maleki, Shohreh

AU - Franco-Cereceda, Anders

AU - Eriksson, Per

PY - 2018/2/9

Y1 - 2018/2/9

N2 - 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 intimamedia tissue samples, and in EA. hy926 and primary aortic endothelial cells (ECs) isolated from BAV and TAV exposed to oscillatory (+/- 12 dynes/cm(2)) or laminar (12 dynes/cm(2)) 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/beta-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.

AB - 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 intimamedia tissue samples, and in EA. hy926 and primary aortic endothelial cells (ECs) isolated from BAV and TAV exposed to oscillatory (+/- 12 dynes/cm(2)) or laminar (12 dynes/cm(2)) 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/beta-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.

KW - MODULATES ENDOTHELIAL REGULATION

KW - MUSCLE-CELL PROLIFERATION

KW - SHEAR-STRESS

KW - MOLECULAR-MECHANISMS

KW - ANEURYSM DEVELOPMENT

KW - REGULATORY REGIONS

KW - NEURAL CREST

KW - NEW-MODEL

KW - IN-VITRO

KW - DISEASE

UR - http://www.nature.com/articles/s41598-018-20642-4

UR - http://www.mendeley.com/research/altered-dna-methylation-indicates-oscillatory-flow-mediated-epithelialtomesenchymal-transition-signa

U2 - 10.1038/s41598-018-20642-4

DO - 10.1038/s41598-018-20642-4

M3 - статья

VL - 8

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 2777

ER -