A cell-autonomous role of Cited2 in controlling myocardial and coronary vascular development

Journal article

Aims 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 (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 results A 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.

Conclusions This 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.

Authors: Macdonald, S; Bamforth, S; Braganc, J; Chen, C; Broadbent, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Oxford University Press
• Journal: European Heart Journal
• Volume: In press
• Issue: 32
• Pages: 2557-2565
• Publication date: 2012-01-01
• DOI: 10.1093/eurheartj/ehs056
• EISSN: 1522-9645
• ISSN: 0195-668X
• Language: English
• Keywords: CITED2; Myocardial development; VEGFA; Capillary growth
• Subjects: Cardiovascular Medicine