Mechanical causes behind congenital heart defect under new focus

Work in Jessica Wagenseil’s lab targets new drug strategies

Beth Miller 12.07.2022

Jessica Wagenseil and her team will take a closer look at the mechanics on smooth muscle cells in the aortic wall with a new NIH grant. (Credit: Wagenseil lab)

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Mutations in the elastin gene are believed to be behind supravalvular aortic stenosis (SVAS), a genetic defect that causes narrowing of the aorta, thus increasing the risk of sudden cardiac death. But there may be an additional contributor to this rare genetic disorder, for which there is no pharmaceutical treatment.

Jessica Wagenseil, professor of mechanical engineering & materials science in the McKelvey School of Engineering at Washington University in St. Louis, plans to look at the role of altered mechanics on smooth muscle cells in the aortic wall with a four-year, $1.6 million grant from the National Institutes of Health. Results of this work may help to identify new drug strategies that could prevent some of these changes.

Wagenseil, also vice dean for faculty advancement, has long studied elastin, a protein that is a key component of a network of elastic fibers that allows the aorta to expand and contract in response to mechanical strain, such as blood pressure. Building on that work, she and her lab will look at changes in the way smooth muscle cells convert a mechanical stimulus, such as strain, if there has not been enough elastin laid down during development needed to stiffen the aortic wall.

“We hypothesize that increased strain on the smooth muscle cells causes activation or overexpression of the protein Piezo2, which leads to downstream signaling events that contribute to stenosis,” Wagenseil said.

Wagenseil and her team will test their theory in a mouse model and in human smooth muscle cells taken from patients with SVAS. They will look at strain under different conditions at various points in development, measure Piezo2 activity in mouse and human smooth muscle cells under strain and manipulate genetic activity in mouse aorta and mouse and human smooth muscle cells to determine its effects on the severity of stenosis.

The McKelvey School of Engineering at Washington University in St. Louis promotes independent inquiry and education with an emphasis on scientific excellence, innovation and collaboration without boundaries. McKelvey Engineering has top-ranked research and graduate programs across departments, particularly in biomedical engineering, environmental engineering and computing, and has one of the most selective undergraduate programs in the country. With 165 full-time faculty, 1,420 undergraduate students, 1,614 graduate students and 21,000 living alumni, we are working to solve some of society’s greatest challenges; to prepare students to become leaders and innovate throughout their careers; and to be a catalyst of economic development for the St. Louis region and beyond.