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

Deficiency of elastin (ELN), the major component of elastic fibers, leads to excess smooth muscle cells (SMCs), which characterizes arterial diseases (for example, supravalvular aortic stenosis (SVAS)) as well as physiological ductus arteriosus (DA) closure. Here we demonstrate that sphingosine kinase 1 (SPHK1) is a key node in these contexts. Sphk1 is the most upregulated transcript in Eln(-/-) aortic SMCs at embryonic day 15.5 when these cells are initially hyperproliferative. The aorta of humans with SVAS also upregulates SPHK1. Reduced ELN increases levels of transcription factor early growth response 1, resulting in increased SPHK1 levels. SMC-specific Sphk1 deletion or pharmacological inhibition of SPHK1 attenuates SMC proliferation and mitigates aortic disease. Furthermore, treatment with a SPHK1 inhibitor reduces DA SMC accumulation, leading to DA patency in wild-type mice. These findings indicate that inhibiting SPHK1 may be a therapeutic strategy for SVAS and select congenital heart diseases in which patent DA maintains circulation.