S1PR1-MYPT1 Maintains Coronary Endothelial Barrier in Pressure-Overloaded Hearts

Coronary microvascular hyperpermeability and the subsequent inflammation infiltration are the key early characteristics of pressure overload-induced myocardial injury. However, how changes in the coronary endothelial barrier function in response to cardiac pressure overload are less explored. Here, we investigated the specific role of S1PR1 (sphingosine-1-phosphate receptor type 1) on coronary endothelial permeability and the signaling pathways involved during pressure overload.

Mice with endothelial deletion of S1PR1 or MYPT1 (myosin phosphatase target subunit 1) were subjected to transverse aortic constriction. We also studied cultured human umbilical vein endothelial cells (ECs) in vitro.

We found upregulated S1PR1 in cardiac ECs at 24 hours and 3 days after transverse aortic constriction, and EC-specific deletion of S1PR1 (S1pr1^ΔEC) led to coronary endothelial hyperpermeability, myocardial edema, and inflammatory infiltration in mice subjected to transverse aortic constriction. In cultured human umbilical vein ECs, silencing S1PR1 reduced total MYPT1 but increased phosphorylated MYPT1, and under TNF-α (tumor necrosis factor-α) stimulation led to MLC (myosin light chain) phosphorylation and actin cytoskeletal contraction. Although S1PR1-NFATc2 (Nuclear Factor of Activated T Cells 2) signaling was essential for maintaining MYPT1 expression, S1PR1 deficiency increased TRPV4 (transient receptor potential vanilloid 4) expression, enhancing extracellular Ca²⁺ entry and MYPT1 phosphorylation. Mice with EC-specifically MYPT1-deficient (Mypt1^ΔEC) also showed coronary endothelial hyperpermeability, and treatment with the S1PR1 agonist FTY720 failed in alleviating the pathological effects. At 1 month post-transverse aortic constriction, both Mypt1^ΔEC and S1pr1^ΔEC mice displayed aggravated pathological cardiac remodeling.

These findings suggest that the S1PR1-MYPT1 signaling is crucial for coronary endothelial permeability and myocardial microenvironmental homeostasis under pressure overload, targeting which may offer therapeutic potential for related heart diseases.