Tbx5 is required for avian and Mammalian epicardial formation and coronary vasculogenesis.

TitleTbx5 is required for avian and Mammalian epicardial formation and coronary vasculogenesis.
Publication TypeJournal Article
Year of Publication2014
AuthorsDiman NYS-G, Brooks G, Kruithof BPT, Elemento O, Seidman JG, Seidman CE, Basson CT, Hatcher CJ
JournalCirc Res
Date Published2014 Oct 24
KeywordsAnimals, Cell Movement, Chick Embryo, Coronary Vessels, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Organogenesis, Pericardium, Species Specificity, T-Box Domain Proteins

RATIONALE: Holt-Oram syndrome is an autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. Overexpression of Tbx5 in the chick proepicardial organ impaired coronary blood vessel formation. However, the potential activity of Tbx5 in the epicardium itself, and the role of Tbx5 in mammalian coronary vasculogenesis, remains largely unknown.

OBJECTIVE: To evaluate the consequences of altered Tbx5 gene dosage during proepicardial organ and epicardial development in the embryonic chick and mouse.

METHODS AND RESULTS: Retroviral-mediated knockdown or upregulation of Tbx5 expression in the embryonic chick proepicardial organ and proepicardial-specific deletion of Tbx5 in the embryonic mouse (Tbx5(epi-/)) impaired normal proepicardial organ cell development, inhibited epicardial and coronary blood vessel formation, and altered developmental gene expression. The generation of epicardial-derived cells and their migration into the myocardium were impaired between embryonic day (E) 13.5 to 15.5 in mutant hearts because of delayed epicardial attachment to the myocardium and subepicardial accumulation of epicardial-derived cells. This caused defective coronary vasculogenesis associated with impaired vascular smooth muscle cell recruitment and reduced invasion of cardiac fibroblasts and endothelial cells into myocardium. In contrast to wild-type hearts that exhibited an elaborate ventricular vascular network, Tbx5(epi-/-) hearts displayed a marked decrease in vascular density that was associated with myocardial hypoxia as exemplified by hypoxia inducible factor-1α upregulation and increased binding of hypoxyprobe-1. Tbx5(epi-/-) mice with such myocardial hypoxia exhibited reduced exercise capacity when compared with wild-type mice.

CONCLUSIONS: Our findings support a conserved Tbx5 dose-dependent requirement for both proepicardial and epicardial progenitor cell development in chick and in mouse coronary vascular formation.

Alternate JournalCirc. Res.
PubMed ID25245104
PubMed Central IDPMC4727243
Grant ListR01 HL80663 / HL / NHLBI NIH HHS / United States
RC1 HL100579 / HL / NHLBI NIH HHS / United States
K01 HL080948 / HL / NHLBI NIH HHS / United States
R01 HL080663 / HL / NHLBI NIH HHS / United States
U01 HL098166 / HL / NHLBI NIH HHS / United States
5U01HL098166 / HL / NHLBI NIH HHS / United States