CD109 Exhibits A Dynamic Expression Pattern in Coronary Endothelium and Endocardial-derived Valve Mesenchyme During Heart Development with Preserved Morphogenesis Following Endothelial-specific Deletion

Andrew B Harvey; Jenna R Drummond; Hannah G Tarolli; Renélyn A Wolters; Raymond N Deepe; Inara Devji; Jeremy L Barth; Robin Muise-Helmericks; Paula S Ramos; Russell A Norris; Andy Wessels;

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ABSTRACT

encodes a GPI-linked glycoprotein that acts as a signaling modulator in the TGF-β pathway. has emerged in several genome-wide association studies as linked to coronary artery disease, myocardial infarction, and angina pectoris. Heterozygous loss-of-function mutations in have also been reported in patients with congenital heart defects, suggesting potential developmental relevance, though has never been investigated in the context of cardiovascular development. We previously identified upregulation in murine atrioventricular valves undergoing myxomatous degeneration following a reduction of epicardial-derived cells. Here, we characterize expression in the murine cardiovascular system and assess its function during development using and approaches. We found that is strongly expressed in the endothelium of the coronary vasculature and in endocardial-derived subpopulations in the atrioventricular valves. This expression persists through key stages in cardiovascular development. Western blotting and immunostaining confirm endothelial expression in heart and lung tissues. siRNA-mediated knockdown of CD109 in primary human endothelial cells led to dysregulation of vascular development pathways and decreased tube formation capacity. We generated endothelial-specific knockout mice, eliminating expression from heart and lung tissues without overt consequences for atrioventricular valve or coronary vascular morphogenesis during heart development. CD109 exhibits a highly dynamic spatiotemporal expression pattern during cardiovascular development, with enriched expression in coronary endothelial cells and endocardial-derived subpopulations in the valves. Despite this striking developmental expression pattern, previously reported human genetic associations with cardiovascular diseases, and endothelial-associated phenotypes following siRNA-mediated CD109 knockdown in a primary human endothelial cell line, endothelial/endocardial-lineage deletion of did not produce overt abnormalities in atrioventricular valve or coronary vascular morphogenesis during embryonic development. Collectively, these findings identify CD109 as a useful marker of coronary endothelial and endocardial-derived valve cell populations and suggest that CD109 may function in a context-dependent or modulatory manner rather than as an essential regulator of cardiovascular morphogenesis under normal developmental conditions.

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