A cell-autonomous role of Cited2 in controlling myocardial and coronary vascular development
<p><strong>Aims</strong> Myocardial development is dependent on concomitant growth of cardiomyocytes and a supporting vascular network. The coupling of myocardial and coronary vascular development is partly mediated by vascular endothelial growth factor (<em>VEGFA</em>)...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Oxford University Press
2012
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| _version_ | 1797053350810746880 |
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| author | Macdonald, S Bamforth, S Braganc, J Chen, C Broadbent, C Schneider, J Schwartz, R Bhattacharya, S Bragança, J |
| author_facet | Macdonald, S Bamforth, S Braganc, J Chen, C Broadbent, C Schneider, J Schwartz, R Bhattacharya, S Bragança, J |
| author_sort | Macdonald, S |
| collection | OXFORD |
| description | <p><strong>Aims</strong> Myocardial development is dependent on concomitant growth of cardiomyocytes and a supporting vascular network. The coupling of myocardial and coronary vascular development is partly mediated by vascular endothelial growth factor (<em>VEGFA</em>) signalling and additional unknown mechanisms. We examined the cardiomyocyte specific role of the transcriptional co-activator <em>Cited2</em> on myocardial microstructure and vessel growth, in relation to <em>Vegfa</em> expression.</p> <p><strong>Methods and results</strong> A cardiomyocyte-specific knockout of mouse <em><em>Cited2</em></em> (<em>Cited2<sup>Nkx</sup></em>) was analysed using magnetic resonance imaging and histology. Ventricular septal defects and significant compact layer thinning (<em>P</em>< 0.02 at right ventricular apex, <em>P</em>< 0.009 at the left ventricular apex in <em>Cited2<sup>Nkx</sup></em> vs. controls, n= 11 vs. n= 7, respectively) were found. This was associated with a significant decrease in the number of capillaries to larger vessels (ratio 1.56 ± 0.56 vs. 3.25 ± 1.63, <em>P</em>= 2.7 × 10<sup>-6</sup> <em>Cited2<sup>Nkx</sup></em> vs. controls, n= 11 vs. n= 7, respectively) concomitant with a 1.5-fold reduction in <em>Vegfa</em> expression (<em>P</em>< 0.02, <em>Cited2<sup>Nkx</sup></em> vs. controls, n= 12 vs. n= 12, respectively). <em>Cited2</em> was subsequently found at the <em>Vegfa</em> promoter in mouse embryonic hearts using chromatin immunoprecipitation, and moreover found to stimulate human <em>VEGFA</em> promoter activity in cooperation with TFAP2 transcription factors in transient transfection assays. There was no change in the myocardial expression of the left-right patterning gene Pitx2c, a previously known target of <em>Cited2</em>.</p> <p><strong>Conclusions</strong> This study delineates a novel cell-autonomous role of <em>Cited2</em> in regulating <em>VEGFA</em> transcription and the development of myocardium and coronary vasculature in the mouse. We suggest that coupling of myocardial and coronary growth in the developing heart may occur in part through a <em>Cited2</em>→<em>Vegfa</em> pathway.</p> |
| first_indexed | 2024-03-06T18:42:36Z |
| format | Journal article |
| id | oxford-uuid:0d693fd3-da50-4bda-b4cf-61f8a32589f9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:42:36Z |
| publishDate | 2012 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:0d693fd3-da50-4bda-b4cf-61f8a32589f92022-03-26T09:40:23ZA cell-autonomous role of Cited2 in controlling myocardial and coronary vascular developmentJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0d693fd3-da50-4bda-b4cf-61f8a32589f9Cardiovascular MedicineEnglishSymplectic Elements at OxfordOxford University Press2012Macdonald, SBamforth, SBraganc, JChen, CBroadbent, CSchneider, JSchwartz, RBhattacharya, SBragança, J<p><strong>Aims</strong> Myocardial development is dependent on concomitant growth of cardiomyocytes and a supporting vascular network. The coupling of myocardial and coronary vascular development is partly mediated by vascular endothelial growth factor (<em>VEGFA</em>) signalling and additional unknown mechanisms. We examined the cardiomyocyte specific role of the transcriptional co-activator <em>Cited2</em> on myocardial microstructure and vessel growth, in relation to <em>Vegfa</em> expression.</p> <p><strong>Methods and results</strong> A cardiomyocyte-specific knockout of mouse <em><em>Cited2</em></em> (<em>Cited2<sup>Nkx</sup></em>) was analysed using magnetic resonance imaging and histology. Ventricular septal defects and significant compact layer thinning (<em>P</em>< 0.02 at right ventricular apex, <em>P</em>< 0.009 at the left ventricular apex in <em>Cited2<sup>Nkx</sup></em> vs. controls, n= 11 vs. n= 7, respectively) were found. This was associated with a significant decrease in the number of capillaries to larger vessels (ratio 1.56 ± 0.56 vs. 3.25 ± 1.63, <em>P</em>= 2.7 × 10<sup>-6</sup> <em>Cited2<sup>Nkx</sup></em> vs. controls, n= 11 vs. n= 7, respectively) concomitant with a 1.5-fold reduction in <em>Vegfa</em> expression (<em>P</em>< 0.02, <em>Cited2<sup>Nkx</sup></em> vs. controls, n= 12 vs. n= 12, respectively). <em>Cited2</em> was subsequently found at the <em>Vegfa</em> promoter in mouse embryonic hearts using chromatin immunoprecipitation, and moreover found to stimulate human <em>VEGFA</em> promoter activity in cooperation with TFAP2 transcription factors in transient transfection assays. There was no change in the myocardial expression of the left-right patterning gene Pitx2c, a previously known target of <em>Cited2</em>.</p> <p><strong>Conclusions</strong> This study delineates a novel cell-autonomous role of <em>Cited2</em> in regulating <em>VEGFA</em> transcription and the development of myocardium and coronary vasculature in the mouse. We suggest that coupling of myocardial and coronary growth in the developing heart may occur in part through a <em>Cited2</em>→<em>Vegfa</em> pathway.</p> |
| spellingShingle | Cardiovascular Medicine Macdonald, S Bamforth, S Braganc, J Chen, C Broadbent, C Schneider, J Schwartz, R Bhattacharya, S Bragança, J A cell-autonomous role of Cited2 in controlling myocardial and coronary vascular development |
| title | A cell-autonomous role of Cited2 in controlling myocardial and coronary vascular development |
| title_full | A cell-autonomous role of Cited2 in controlling myocardial and coronary vascular development |
| title_fullStr | A cell-autonomous role of Cited2 in controlling myocardial and coronary vascular development |
| title_full_unstemmed | A cell-autonomous role of Cited2 in controlling myocardial and coronary vascular development |
| title_short | A cell-autonomous role of Cited2 in controlling myocardial and coronary vascular development |
| title_sort | cell autonomous role of cited2 in controlling myocardial and coronary vascular development |
| topic | Cardiovascular Medicine |
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