Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart.
Heart valve anomalies are some of the most common congenital heart defects, yet neither the genetic nor the epigenetic forces guiding heart valve development are well understood. When functioning normally, mature heart valves prevent intracardiac retrograde blood flow; before valves develop, there i...
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Public Library of Science (PLoS)
2009-11-01
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| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1000246&type=printable |
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| author | Julien Vermot Arian S Forouhar Michael Liebling David Wu Diane Plummer Morteza Gharib Morteza Gharib Scott E Fraser |
| author_facet | Julien Vermot Arian S Forouhar Michael Liebling David Wu Diane Plummer Morteza Gharib Morteza Gharib Scott E Fraser |
| author_sort | Julien Vermot |
| collection | DOAJ |
| description | Heart valve anomalies are some of the most common congenital heart defects, yet neither the genetic nor the epigenetic forces guiding heart valve development are well understood. When functioning normally, mature heart valves prevent intracardiac retrograde blood flow; before valves develop, there is considerable regurgitation, resulting in reversing (or oscillatory) flows between the atrium and ventricle. As reversing flows are particularly strong stimuli to endothelial cells in culture, an attractive hypothesis is that heart valves form as a developmental response to retrograde blood flows through the maturing heart. Here, we exploit the relationship between oscillatory flow and heart rate to manipulate the amount of retrograde flow in the atrioventricular (AV) canal before and during valvulogenesis, and find that this leads to arrested valve growth. Using this manipulation, we determined that klf2a is normally expressed in the valve precursors in response to reversing flows, and is dramatically reduced by treatments that decrease such flows. Experimentally knocking down the expression of this shear-responsive gene with morpholine antisense oligonucleotides (MOs) results in dysfunctional valves. Thus, klf2a expression appears to be necessary for normal valve formation. This, together with its dependence on intracardiac hemodynamic forces, makes klf2a expression an early and reliable indicator of proper valve development. Together, these results demonstrate a critical role for reversing flows during valvulogenesis and show how relatively subtle perturbations of normal hemodynamic patterns can lead to both major alterations in gene expression and severe valve dysgenesis. |
| format | Article |
| id | doaj-art-954f9d94a673490cbbd9d8a4407b60e7 |
| institution | OA Journals |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2009-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-954f9d94a673490cbbd9d8a4407b60e72025-08-20T02:12:59ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852009-11-01711e100024610.1371/journal.pbio.1000246Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart.Julien VermotArian S ForouharMichael LieblingDavid WuDiane PlummerMorteza GharibMorteza GharibScott E FraserHeart valve anomalies are some of the most common congenital heart defects, yet neither the genetic nor the epigenetic forces guiding heart valve development are well understood. When functioning normally, mature heart valves prevent intracardiac retrograde blood flow; before valves develop, there is considerable regurgitation, resulting in reversing (or oscillatory) flows between the atrium and ventricle. As reversing flows are particularly strong stimuli to endothelial cells in culture, an attractive hypothesis is that heart valves form as a developmental response to retrograde blood flows through the maturing heart. Here, we exploit the relationship between oscillatory flow and heart rate to manipulate the amount of retrograde flow in the atrioventricular (AV) canal before and during valvulogenesis, and find that this leads to arrested valve growth. Using this manipulation, we determined that klf2a is normally expressed in the valve precursors in response to reversing flows, and is dramatically reduced by treatments that decrease such flows. Experimentally knocking down the expression of this shear-responsive gene with morpholine antisense oligonucleotides (MOs) results in dysfunctional valves. Thus, klf2a expression appears to be necessary for normal valve formation. This, together with its dependence on intracardiac hemodynamic forces, makes klf2a expression an early and reliable indicator of proper valve development. Together, these results demonstrate a critical role for reversing flows during valvulogenesis and show how relatively subtle perturbations of normal hemodynamic patterns can lead to both major alterations in gene expression and severe valve dysgenesis.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1000246&type=printable |
| spellingShingle | Julien Vermot Arian S Forouhar Michael Liebling David Wu Diane Plummer Morteza Gharib Morteza Gharib Scott E Fraser Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart. PLoS Biology |
| title | Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart. |
| title_full | Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart. |
| title_fullStr | Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart. |
| title_full_unstemmed | Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart. |
| title_short | Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart. |
| title_sort | reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1000246&type=printable |
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