Document Type
Article
Publication Date
9-22-2014
Abstract
Rationale: Holt-Oram syndrome (HOS) is an autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. Overexpression of Tbx5 in the chick proepicardial organ (PEO) impaired coronary blood vessel formation. However, the potential activity of Tbx5 in the epicardium itself, and Tbx5's role in mammalian coronary vasculogenesis, remains largely unknown. Objective: To evaluate the consequences of altered Tbx5 gene dosage during PEO and epicardial development in the embryonic chick and mouse. Methods and Results: Retroviral-mediated knockdown or upregulation of Tbx5 expression in the embryonic chick PEO as well as proepicardial-specific deletion of Tbx5 in the embryonic mouse (Tbx5(epi-/-)) impaired normal PEO cell development, inhibited epicardial and coronary blood vessel formation and altered developmental gene expression. The generation of epicardial-derived cells (EPDCs) and their migration into the myocardium was impaired between embryonic day (E) 13.5-15.5 in mutant hearts due to delayed epicardial attachment to the myocardium and subepicardial accumulation of EPDCs. 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 wildtype 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 HIF1α upregulation and increased binding of Hypoxyprobe-1. Tbx5(epi-/-) mice with such myocardial hypoxia exhibited reduced exercise capacity compared to wildtype mice. Conclusions: Our findings support a conserved Tbx5 dose-dependent requirement for both proepicardial and epicardial progenitor cell development in chick and mouse coronary vascular formation.
Publication Title
Circulation research
Volume
115
Issue
ePub
PubMed ID
25245104
Recommended Citation
Diman, Nata Y; Brooks, Gabriel; Kruithof, Boudewijn P; Elemento, Olivier; Seidman, Jonathan G; Seidman, Christine; Basson, Craig T; and Hatcher, Cathy J., "Tbx5 is Required for Avian and Mammalian Epicardial Formation and Coronary Vasculogenesis." (2014). PCOM Scholarly Works. 243.
https://digitalcommons.pcom.edu/scholarly_papers/243
Comments
This article was published online in Circulation Research.
The published version is available at http://dx.doi.org/10.1161/CIRCRESAHA.115.304379
Copyright © 2014 by the American Heart Association