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Developmental Regulation of Epicardial Cell Adhesion and Coronary Vasculogenesis

Mutations in the gene encoding the TBX5 transcription factor cause Holt‐Oram syndrome (HOS). Individuals with HOS exhibit structural congenital heart defects that affect formation of the pericardium and coronary vessels. These structures descend from cells that migrate out of the transitory proepicardium during early cardiogenesis. Our previous analyses revealed that Tbx5 is expressed in the proepicardium, visceral pericardium/epicardium and coronary vessels. Analyses of mice with proepicardial‐specific deletion of Tbx5 (Tbx5epi‐/‐) revealed that Tbx5 contributes to epicardial cell adhesion to the myocardium and epicardial‐derived cell migration into the myocardium to form coronary vessels. Genes encoding cell adhesion and extracellular matrix (ECM) proteins were decreased in Tbx5epi‐/‐mouse hearts. These cell adhesion and ECM proteins have established roles in extracardiac tissues, but their functional roles in cardiovascular development remain unknown. Our current study aims to identify cardiovascular developmental regulation of these genes. We demonstrate that Tbx5 regulates transcription of genes encoding these cell adhesion and ECM proteins. Our analyses also reveal that proteins encoded by these Tbx5‐dependent genes are detected as early as embryonic day 11.5 in the developing heart. Cardiac expression of these proteins correlates with formation of the epicardium and coronary vessels. Further studies will determine the requisite functional contributions of the cell adhesion and ECM proteins to establishment and maintenance of the epicardium and underlying coronary vessels. (Support: PCOM Center for Chronic Disorders of Aging)