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Vascular Sphingosine Kinase 1 Regulates Angiotensin II-Induced Hypertension
Ewelina Jozefczuk1, Piotr Szczepaniak1, Tomasz P Mikolajczyk1
1Department of Internal Medicine, Faculty of Medicine (E.J., P.S., T.P.M., M.D., K.U., E.W., T.J.G., M. Siedlinski), Jagiellonian University Medical College, Cracow, Poland.
Hypertension (Dallas, Tex. : 1979)
|April 7, 2026
Summary
Sphingosine kinase 1 (Sphk1) in smooth muscle cells drives hypertension. Deleting Sphk1 in these cells protects against angiotensin II-induced high blood pressure by reducing myogenic tone.
Area of Science:
- Cardiovascular Biology
- Vascular Physiology
- Molecular Medicine
Background:
- Sphingosine-1-phosphate (S1P) signaling is crucial for cardiovascular regulation.
- Upregulated sphingosine kinase 1 (Sphk1) in arterial hypertension (HTN) suggests a role in disease pathogenesis.
- Global Sphk1 deletion alleviates angiotensin II (AngII)-induced HTN, but cellular mechanisms are unclear.
Purpose of the Study:
- To elucidate the specific cellular roles of Sphk1 in smooth muscle cells (SMCs) and endothelial cells (ECs) in AngII-induced HTN.
- To investigate the molecular pathways by which Sphk1 influences vascular function and blood pressure regulation.
Main Methods:
- Generated SMC-specific and EC-specific Sphk1 knockout mice using Cre-loxP technology.
- Induced hypertension via AngII infusion and assessed blood pressure, vascular structure, and function using myography and histology.
- Utilized RNA sequencing, Gene Set Enrichment Analysis, RT-qPCR, and Western blotting to identify underlying molecular mechanisms.
Main Results:
- SMC-specific Sphk1 deletion significantly protected against AngII-induced HTN, lowering systolic blood pressure compared to controls.
- EC-specific Sphk1 knockout did not prevent HTN development.
- Reduced myogenic tone and Rho-associated protein kinase (Rock1/2) expression in mesenteric arteries of SMC-Sphk1 knockout mice were observed.
- Despite protection from HTN, SMC-Sphk1 knockout mice showed arterial stiffness and impaired vasorelaxation linked to fibronectin 1 (Fn1) deposition.
Conclusions:
- Sphk1 derived from smooth muscle cells plays a critical role in mediating angiotensin II-induced hypertension, primarily by modulating myogenic tone.
- Fibronectin 1 deposition in arteries of SMC-Sphk1 knockout mice suggests a complex interplay between Sphk1, vascular structure, and function.
- Targeting SMC Sphk1 may offer a therapeutic strategy for hypertension, warranting further investigation into its downstream effects.
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