Ding, K.; Xu, B.; Yu, X.; Jia, X.; Li, T.; Shen, X.; Li, J.; Cao, X.; Liu, Y.; Zhang, Z.; He, Y.

Atrial cardiomyopathy is characterized by altered atrial structures and the genetic basis underlying the disorders remains inadequately explored. TIE1 variants or loss of function mutations were reported in a subset of lymphedema patients, and it is unknown whether the patients have also cardiac defects in addition to the lymphatic abnormality. We show in this study that endothelial Tie1 and Tek are highly expressed in endocardial cells of atria by the single cell RNA-seq analysis. TIE1 deficiency led to the disruption of atrial morphogenesis with minor defects in the ventricles. The bulk RNA-seq analysis of hearts at the four-chambered stage revealed that gene transcripts related to endothelial cell development and cardiac trabeculation were reduced in the Tie1 mutant mice compared with littermate controls. This was further confirmed by the RNA-seq analysis of atria and ventricles separately, showing more trabecular genes downregulated in the atria including Tek, upon the loss of Tie1. Consistent with the scRNA-seq data, we found that Tie1 and Tek transcripts were higher in atria than in ventricles. Furthermore, the endothelial deletion of Tek resulted in the defective formation of cardiac trabeculae, particularly in atria. Consistently, the loss of Tie1 combined with one null allele of Tek disrupted both atrial and ventricular trabeculation. Surprisingly, defects with the atrial chamber morphogenesis were already detectable 48 hours later upon the induced endothelial loss of Tie1 plus the Tek heterozygous deletion, implying a critical role of endocardium in the organization of the atrial internal muscular network. The synergy of TIE1 and TIE2 in the remodeling of atrial trabeculae was further confirmed at the postnatal stage, while TIE1 insufficiency alone had no obvious effect. Together, findings from this study imply that TIE1 is differentially required for the atrial and ventricular development and acts in synergy with TIE2 to regulate the endocardial cell-coordinated atrial internal muscular network assembly.