| A cell-autonomous role of Cited2 in controlling myocardial and coronary vascular development. | |
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MedLine Citation:
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PMID: 22504313 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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AimsMyocardial 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 (VEGFA) signalling and additional unknown mechanisms. We examined the cardiomyocyte specific role of the transcriptional co-activator Cited2 on myocardial microstructure and vessel growth, in relation to Vegfa expression.Methods and resultsA cardiomyocyte-specific knockout of mouse Cited2 (Cited2(Nkx)) was analysed using magnetic resonance imaging and histology. Ventricular septal defects and significant compact layer thinning (P< 0.02 at right ventricular apex, P< 0.009 at the left ventricular apex in Cited2(Nkx) 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, P= 2.7 × 10(-6) Cited2(Nkx) vs. controls, n= 11 vs. n= 7, respectively) concomitant with a 1.5-fold reduction in Vegfa expression (P< 0.02, Cited2(Nkx) vs. controls, n= 12 vs. n= 12, respectively). CITED2 was subsequently found at the Vegfa promoter in mouse embryonic hearts using chromatin immunoprecipitation, and moreover found to stimulate human VEGFA 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 CITED2.ConclusionsThis study delineates a novel cell-autonomous role of Cited2 in regulating VEGFA 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 Cited2→Vegfa pathway. |
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Authors:
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Simon T Macdonald; Simon D Bamforth; José Bragança; Chiann-Mun Chen; Carol Broadbent; Jürgen E Schneider; Robert J Schwartz; Shoumo Bhattacharya |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-4-14 |
Journal Detail:
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Title: European heart journal Volume: - ISSN: 1522-9645 ISO Abbreviation: - Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-4-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8006263 Medline TA: Eur Heart J Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Cardiovascular Medicine, University of Oxford and Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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