S1PR1-MYPT1 Maintains Coronary Endothelial Barrier in Pressure-Overloaded Hearts
Xin-Yi Zhao1, Rui Xu2, Jing-Jing Li3
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Shaanxi, China (X.-Y.Z., Y.-P.C., G.S., Z.-D.P., N.H., X.-L.D., X.-J.D., Y.Z.).
Insights
Sphingosine-1-phosphate receptor type 1 (S1PR1) signaling is vital for maintaining coronary endothelial barrier function during cardiac pressure overload. Disrupting S1PR1-MYPT1 signaling exacerbates myocardial injury and cardiac remodeling.
Area of Science:
- Cardiovascular Biology
- Endothelial Cell Biology
- Molecular Cardiology
Background:
- Coronary microvascular hyperpermeability and inflammation are early signs of pressure overload-induced myocardial injury.
- The role of coronary endothelial barrier function changes under pressure overload is not fully understood.
- This study investigates the role of sphingosine-1-phosphate receptor type 1 (S1PR1) in endothelial permeability during pressure overload.
Purpose of the Study:
- To elucidate the specific role of S1PR1 in coronary endothelial permeability under pressure overload.
- To identify the signaling pathways regulated by S1PR1 in cardiac endothelial cells.
- To explore the therapeutic potential of targeting S1PR1-MYPT1 signaling in heart disease.
Main Methods:
- Utilized mouse models with endothelial-specific deletion of S1PR1 or MYPT1 subjected to transverse aortic constriction.
- Employed cultured human umbilical vein endothelial cells (ECs) for in vitro experiments.
- Analyzed S1PR1 expression, MYPT1 phosphorylation, and downstream signaling pathways.
Main Results:
- Endothelial S1PR1 was upregulated post-pressure overload; its deletion caused hyperpermeability, edema, and inflammation.
- S1PR1 deficiency in ECs altered MYPT1 phosphorylation and increased TRPV4 expression, leading to calcium influx.
- Endothelial MYPT1 deficiency also resulted in hyperpermeability, and S1PR1 agonist treatment was ineffective.
- Both S1PR1- and MYPT1-deficient mice showed aggravated cardiac remodeling after pressure overload.
Conclusions:
- The S1PR1-MYPT1 signaling axis is essential for maintaining coronary endothelial permeability and myocardial homeostasis under pressure overload.
- Targeting this pathway may offer a novel therapeutic strategy for pressure overload-induced heart conditions.
- Understanding endothelial barrier regulation is critical for preventing cardiac injury and remodeling.
Background:
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.
Methods:
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.
Results:
We found upregulated S1PR1 in cardiac ECs at 24 hours and 3 days after transverse aortic constriction, and EC-specific deletion of S1PR1 (S1pr1ΔEC) 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 (Mypt1ΔEC) 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 Mypt1ΔEC and S1pr1ΔEC mice displayed aggravated pathological cardiac remodeling.
Conclusions:
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.
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