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Sphingosine 1‐Phosphate receptor 1 (S1P 1 , encoded by S1pr1 ) is a G protein‐coupled receptor that signals in multiple cell types including endothelial cells and cardiomyocytes. Cardiomyocyte‐specific deletion of S1pr1 during mouse development leads to ventricular noncompaction, with 44% of mutant mice surviving to adulthood. Adult survivors of embryonic cardiomyocyte S1pr1 deletion showed cardiac hypertrabeculation consistent with ventricular noncompaction. Surprisingly, systolic function in mutant mice was preserved through at least 1 year of age. Cardiac conduction was abnormal in cardiomyocyte S1pr1 mutant mice, with prolonged QRS intervals in mutants as compared with littermate control mice. Immunostaining of hearts from S1pr1 mutant embryos displayed a zone of intermediate Connexin 40 (Cx40) expression in the trabecular myocardium. However, we observed no significant differences in Cx40 and Connexin 43 immunostaining in hearts from adult survivors of embryonic cardiomyocyte S1pr1 deletion, which suggests normalized development of the ventricular conduction system in mutant mice. By contrast, the adult survivors of embryonic cardiomyocyte S1pr1 deletion showed increased cardiac fibrosis as compared with littermate controls. These results demonstrate that ventricular hypertrabeculation caused by embryonic deletion of cardiomyocyte S1pr1 correlates with cardiac fibrosis, which contributes to abnormal ventricular conduction. These results also reveal conduction abnormalities in the setting of hypertrabeculation with normal systolic function, which may be of clinical relevance in humans with ventricular hypertrabeculation.

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Sphingosine 1-phosphate receptor 1 (S1P 1 , encoded by S1pr1 ) is a G protein-coupled receptor that binds the ligand S1P and signals in multiple cell types including endothelium and cardiomyocytes. We previously demonstrated that excision of S1pr1 in cardiomyocytes during embryonic development leads to ventricular noncompaction and perinatal death in most but not all mutant mice. To investigate roles for S1P 1 in adult cardiomyocytes, we used three conditional S1pr1 deletion strategies. Mice that survived early embryonic deletion of S1pr1 in cardiomyocytes using Mlc2a- Cre demonstrated interstitial cardiac fibrosis by 4 months of age. Animals with later embryonic deletion of cardiomyocyte S1pr1 using αMHC-Cre escaped the ventricular noncompaction phenotype, but they displayed significantly increased interstitial fibrosis after isoproterenol infusion. Likewise, S1pr1 excision from cardiomyocytes in adult mice using αMHC-MerCreMer led to increased cardiac fibrosis after angiotensin II infusion. In all conditional S1pr1 excision strategies, systolic function in mutant mice remained similar to control mice. Finally, we conditionally deleted the sphingosine kinases Sphk1 and Sphk2 in developing cardiomyocytes and found no reduction in survival for cardiomyocyte Sphk1/2 mutant mice. These results suggest that S1P from non-cardiomyocyte sources support cardiac development, and that cardiomyocyte S1P 1 activity protects against cardiac fibrosis.