Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy
Patients with a congenital bicuspid aortic valve (BAV), a valve with two instead of three aortic leaflets, have an increased risk of developing thoracic aneurysms and aortic dissection. The mechanisms underlying BAV-associated aortopathy are poorly understood. This study examined BAV-associated aort...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2020-09-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/13/9/dmm044990 |
| _version_ | 1818340978100011008 |
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| author | Joshua C. Peterson Lambertus J. Wisse Valerie Wirokromo Tessa van Herwaarden Anke M. Smits Adriana C. Gittenberger-de Groot Marie-José T. H. Goumans J. Conny VanMunsteren Monique R. M. Jongbloed Marco C. DeRuiter |
| author_facet | Joshua C. Peterson Lambertus J. Wisse Valerie Wirokromo Tessa van Herwaarden Anke M. Smits Adriana C. Gittenberger-de Groot Marie-José T. H. Goumans J. Conny VanMunsteren Monique R. M. Jongbloed Marco C. DeRuiter |
| author_sort | Joshua C. Peterson |
| collection | DOAJ |
| description | Patients with a congenital bicuspid aortic valve (BAV), a valve with two instead of three aortic leaflets, have an increased risk of developing thoracic aneurysms and aortic dissection. The mechanisms underlying BAV-associated aortopathy are poorly understood. This study examined BAV-associated aortopathy in Nos3−/− mice, a model with congenital BAV formation. A combination of histological examination and in vivo ultrasound imaging was used to investigate aortic dilation and dissections in Nos3−/− mice. Moreover, cell lineage analysis and single-cell RNA sequencing were used to observe the molecular anomalies within vascular smooth muscle cells (VSMCs) of Nos3−/− mice. Spontaneous aortic dissections were found in ascending aortas located at the sinotubular junction in ∼13% of Nos3−/− mice. Moreover, Nos3−/− mice were prone to developing aortic dilations in the proximal and distal ascending aorta during early adulthood. Lower volumes of elastic fibres were found within vessel walls of the ascending aortas of Nos3−/− mice, as well as incomplete coverage of the aortic inner media by neural crest cell (NCC)-derived VSMCs. VSMCs of Nos3−/− mice showed downregulation of 15 genes, of which seven were associated with aortic aneurysms and dissections in the human population. Elastin mRNA was most markedly downregulated, followed by fibulin-5 expression, both primary components of elastic fibres. This study demonstrates that, in addition to congenital BAV formation, disrupted endothelial-mediated nitric oxide (NO) signalling in Nos3−/− mice also causes aortic dilation and dissection, as a consequence of inhibited elastic fibre formation in VSMCs within the ascending aorta. |
| first_indexed | 2024-12-13T15:51:29Z |
| format | Article |
| id | doaj.art-63a376b7ba4e4b439c21b82b9eacdf08 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-13T15:51:29Z |
| publishDate | 2020-09-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-63a376b7ba4e4b439c21b82b9eacdf082022-12-21T23:39:28ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112020-09-0113910.1242/dmm.044990044990Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathyJoshua C. Peterson0Lambertus J. Wisse1Valerie Wirokromo2Tessa van Herwaarden3Anke M. Smits4Adriana C. Gittenberger-de Groot5Marie-José T. H. Goumans6J. Conny VanMunsteren7Monique R. M. Jongbloed8Marco C. DeRuiter9 Department of Anatomy and Embryology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands Department of Anatomy and Embryology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands Department of Anatomy and Embryology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands Department of Chemical Cell Biology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands Department of Chemical Cell Biology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands Department of Cardiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands Department of Chemical Cell Biology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands Department of Anatomy and Embryology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands Department of Anatomy and Embryology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands Department of Anatomy and Embryology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands Patients with a congenital bicuspid aortic valve (BAV), a valve with two instead of three aortic leaflets, have an increased risk of developing thoracic aneurysms and aortic dissection. The mechanisms underlying BAV-associated aortopathy are poorly understood. This study examined BAV-associated aortopathy in Nos3−/− mice, a model with congenital BAV formation. A combination of histological examination and in vivo ultrasound imaging was used to investigate aortic dilation and dissections in Nos3−/− mice. Moreover, cell lineage analysis and single-cell RNA sequencing were used to observe the molecular anomalies within vascular smooth muscle cells (VSMCs) of Nos3−/− mice. Spontaneous aortic dissections were found in ascending aortas located at the sinotubular junction in ∼13% of Nos3−/− mice. Moreover, Nos3−/− mice were prone to developing aortic dilations in the proximal and distal ascending aorta during early adulthood. Lower volumes of elastic fibres were found within vessel walls of the ascending aortas of Nos3−/− mice, as well as incomplete coverage of the aortic inner media by neural crest cell (NCC)-derived VSMCs. VSMCs of Nos3−/− mice showed downregulation of 15 genes, of which seven were associated with aortic aneurysms and dissections in the human population. Elastin mRNA was most markedly downregulated, followed by fibulin-5 expression, both primary components of elastic fibres. This study demonstrates that, in addition to congenital BAV formation, disrupted endothelial-mediated nitric oxide (NO) signalling in Nos3−/− mice also causes aortic dilation and dissection, as a consequence of inhibited elastic fibre formation in VSMCs within the ascending aorta.http://dmm.biologists.org/content/13/9/dmm044990nos3aortic dissectionbicuspid aortic valvenitric oxidedevelopmentcongenital heart disease |
| spellingShingle | Joshua C. Peterson Lambertus J. Wisse Valerie Wirokromo Tessa van Herwaarden Anke M. Smits Adriana C. Gittenberger-de Groot Marie-José T. H. Goumans J. Conny VanMunsteren Monique R. M. Jongbloed Marco C. DeRuiter Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy Disease Models & Mechanisms nos3 aortic dissection bicuspid aortic valve nitric oxide development congenital heart disease |
| title | Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy |
| title_full | Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy |
| title_fullStr | Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy |
| title_full_unstemmed | Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy |
| title_short | Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy |
| title_sort | disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy |
| topic | nos3 aortic dissection bicuspid aortic valve nitric oxide development congenital heart disease |
| url | http://dmm.biologists.org/content/13/9/dmm044990 |
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