Researchers Uncover Potential Pathway To Address Williams-Beuren Syndrome

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 at Yale School of Medicine, 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.”

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.”

The first author of the study is Junichi Saito, MD, PhD, a former postdoctoral fellow at Yale and now an assistant professor at Augusta University. Additional study authors include: Jui M. Dave, PhD; Eunate Gallardo-Vara, PhD; Nandhini Sadagopan, PhD; Inamul Kabir, PhD; George Tellides, MD, PhD; Robert K. Riemer, PhD; Zsolt Urban, PhD; Sarah Spiegel, PhD; and Timothy Hla, PhD.