Daniel Greif, MD, professor of medicine (cardiovascular medicine) and genetics
Photo Credit: Courtesy of Yale School of Medicine
Scientific Frontline: Extended "At a Glance" Summary
- The Core Concept: Researchers have identified sphingosine kinase 1 as a critical enzyme that drives the excess growth of smooth muscle cells, a primary cause of life-threatening arterial blockages in patients with Williams-Beuren syndrome.
- Key Distinction/Mechanism: While Williams-Beuren syndrome is caused by a genetic elastin deficiency, this specific enzyme acts as an early "on switch" for the disease's complications. Unlike previously identified markers (such as NOTCH3) that appear later in the disease progression, sphingosine kinase 1 initiates the smooth muscle proliferation that leads to supravalvular aortic stenosis (narrowing of the aorta).
- Origin/History: The findings were published in Nature Cardiovascular Research on January 22, 2026, by a team led by Dr. Daniel Greif at the Yale School of Medicine.
- Major Frameworks/Components:
- Elastin Deficiency: The underlying genetic mutation preventing blood vessels from recoiling properly.
- Sphingosine Kinase 1: The newly identified enzyme target responsible for cell overgrowth.
- Smooth Muscle Proliferation: The biological process causing arterial narrowing.
- Supravalvular Aortic Stenosis: The specific cardiovascular condition resulting from the syndrome.
- Branch of Science: Cardiovascular Medicine, Genetics, and Cell Biology.
- Future Application: The immediate goal is developing pharmaceutical treatments to inhibit this enzyme, offering a non-surgical option for Williams-Beuren patients. Broader applications may include treating other conditions defined by excess smooth muscle, such as atherosclerosis, pulmonary hypertension, and coronary artery restenosis.
- Why It Matters: Currently, there are no pharmacological treatments for Williams-Beuren syndrome; high-risk surgery is the only option. Identifying this early-stage enzymatic trigger provides the first viable pathway for creating a drug that could prevent or reverse the lethal cardiovascular complications of the disease.
Williams-Beuren syndrome is a rare, congenital disease in which the main morbidity and mortality comes from obstructions, or stenoses, in specific arteries. When these obstructions involve the aorta, it is known as supravalvular aortic stenosis. Currently, there are no medications to treat this condition. Although surgery is an option for some patients, not all types of arterial stenosis can be easily corrected with surgery. If left untreated, this condition could result in serious cardiovascular complications, including congestive heart failure.
A new Yale-led study published in Nature Cardiovascular Research provides insights into the development of supravalvular aortic stenosis and identifies a possible pathway for targeting the disorder.
“Supravalvular aortic stenosis is caused by a genetic mutation that makes individuals produce less elastin, a protein that allows blood vessels to recoil like a rubber band,” says Daniel Greif, MD, professor of medicine (cardiovascular medicine) and genetics, and senior author of the study. “This elastin deficiency leads to excess smooth muscle cells and, eventually, stenosis. Our aim for this study was to better understand what causes the accelerated proliferation of smooth muscle cells so that one day potential treatments can be discovered and used for the disorder.”
"Based on our research, we think sphingosine kinase 1 may represent a node that causes those other changes, making it a strong candidate for additional research, and in the future, a possible treatment target to help people with Williams-Beuren syndrome."Daniel Greif, MDProfessor of Medicine (Cardiovascular Medicine)
In this study, investigators in the Greif Lab discovered that a specific enzyme, sphingosine kinase 1, causes excess smooth muscle cells to proliferate. Although prior research by Greif and his team identified other pathways perturbed by elastin deficiency (including the NOTCH3 pathway and the integrin β3 gene), their latest findings indicate that sphingosine kinase 1 is altered early in the developmental process. Changes to NOTCH3 and integrin β3 were observed to occur later.
“Based on our research, we think sphingosine kinase 1 may represent a node that causes those other changes, making it a strong candidate for additional research, and in the future, a possible treatment target to help people with Williams-Beuren syndrome,” says Greif.
Recently published research from other laboratories has shown that this pathway may be relevant to pulmonary hypertension, another condition that is also characterized by excess smooth muscle.
“Williams-Beuren is a rare disease, so it is not an area highly studied by other scientists,” says Greif. “Although more research is needed, we think this pathway may also be important to target for other types of more common cardiovascular disease where there’s excess smooth muscle, such as atherosclerosis or coronary artery restenosis.”
Funding: National Institutes of Health (awards K99HL171838, R00HL171838, R35HL150766, R01HL125815, and R01HD110059). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Published in journal: Nature Cardiovascular Research
Title: Sphingosine kinase 1 is integral for elastin deficiency-induced arterial hypermuscularization
Authors: Junichi Saito, Jui M. Dave, Eunate Gallardo-Vara, Nandhini Sadagopan, Inamul Kabir, George Tellides, Robert K. Riemer, Zsolt Urban, Sarah Spiegel, Timothy Hla, and Daniel M. Greif
Source/Credit: Yale School of Medicine | Rachel Martin
Reference Number: med012526_01