CD109 is dynamically expressed in endothelial and endocardial subpopulations during heart development, modulates endothelial cell behavior in vitro, but is not required for cardiovascular morphogenesis

CD109 encodes a GPI-linked glycoprotein that acts as a signaling modulator in the TGF-β pathway. CD109 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 CD109 have also been reported in patients with congenital heart defects, suggesting potential developmental relevance, though CD109 has never been investigated in the context of cardiovascular development. We previously identified Cd109 upregulation in murine atrioventricular valves undergoing myxomatous degeneration following a reduction of epicardial-derived cells. Here, we characterize Cd109 expression in the murine cardiovascular system and assess its function during development using in vitro and in vivo approaches. We found that Cd109 is strongly expressed in the endothelium of the coronary vasculature and in an endocardial-derived subpopulation 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 knockdown of CD109 in primary human endothelial cells led to dysregulation of vascular development pathways and decreased tube formation capacity. We generated Tie2Cre;Cd109fl/fl mice, eliminating Cd109 expression from heart and lung tissues without overt morphological consequences. Together, these results establish Cd109 as a useful marker of coronary vasculature in the heart and indicate that endothelial lineage-specific deletion of Cd109 does not cause gross morphological defects during cardiac development. The transcriptional and functional changes observed in endothelial cells in vitro suggest that additional studies will be necessary to define contexts in which Cd109 influences vascular biology.