Sphingosine kinase 1 is integral for elastin deficiency-induced arterial hypermuscularization.

Area of Science:

• Vascular Biology
• Molecular Medicine
• Cardiovascular Research

Background:

• Elastin (ELN) deficiency causes smooth muscle cell (SMC) excess, characteristic of arterial diseases such as supravalvular aortic stenosis (SVAS) and ductus arteriosus (DA) closure.
• Early growth response 1 (EGR1) transcription factor levels increase with reduced ELN, leading to elevated sphingosine kinase 1 (SPHK1) expression.

Purpose of the Study:

• To investigate the role of sphingosine kinase 1 (SPHK1) in elastin deficiency-related vascular pathologies.
• To evaluate SPHK1 inhibition as a potential therapeutic approach for supravalvular aortic stenosis (SVAS) and patent ductus arteriosus (PDA).

Main Methods:

• Analysis of Sphk1 gene expression in elastin-deficient mouse models and human SVAS aorta samples.
• SMC-specific Sphk1 deletion and pharmacological SPHK1 inhibition in mouse models.
• Assessment of SMC proliferation, aortic disease progression, and DA patency.

Main Results:

• Sphk1 was the most upregulated transcript in elastin-deficient SMCs and is elevated in human SVAS aortas.
• SMC-specific Sphk1 deletion or SPHK1 inhibition reduced SMC proliferation and mitigated aortic disease.
• SPHK1 inhibition led to reduced SMC accumulation in the DA, promoting DA patency in wild-type mice.

Conclusions:

• SPHK1 is a critical mediator of SMC hyperproliferation in elastin deficiency.
• Targeting SPHK1 presents a promising therapeutic avenue for SVAS and congenital heart diseases requiring a patent DA.