Studying the cells of people and genetically engineered mice, Johns Hopkins Medicine scientists say they have uncovered a potential reason why patients with Loeys-Dietz syndrome, an inherited connective tissue disorder, are especially prone to developing aneurysms at the root of the aorta, the major artery that carries blood away from the heart and to the rest of the body.

Loeys-Dietz syndrome affects the craniofacial, skeletal, cutaneous, gastrointestinal and cardiovascular systems. Aneurysms, an aggressive hallmark of Loeys-Dietz syndrome that occur when a blood vessel’s diameter grows 50% larger than its usual size, are bulging enlargements of an artery that predispose it to life-threatening tears (dissections) or rupture. Although patients with Loeys-Dietz syndrome are at risk of developing aneurysms in all arteries, the base of the aorta closest to the heart is the site at greatest risk, the researchers say.

The findings, published Nov. 20 in Nature Cardiovascular Research, indicate that vascular smooth muscle cells (the muscle cells in blood vessel walls) in the aortic root of mice with this disorder produce excessive amounts of the critical protein Gata4, making them susceptible to aneurysms. 

The mice harbor a genetic mutation in the Tgfbr1 gene, one of seven genes known to be altered in patients with Loeys-Dietz syndrome. The mutation of TGFBR1 was previously observed in patients with this condition, “adding confidence in the relevance of these findings to people with Loeys-Dietz syndrome,” says Hal Dietz III, M.D., the Victor A. McKusick Professor of Medicine and Genetics at the Johns Hopkins University School of Medicine. 

Identifying risk factors for aortic aneurysms in Loeys-Dietz patients has been a central focus of research, says Elena MacFarlane, Ph.D., assistant professor of genetic medicine at Johns Hopkins University School of Medicine.

“In many patients, the aortic root is the canary in the coal mine, the first area of the aorta that dilates, indicating that the vessel is losing its integrity,” MacFarlane says. “Understanding what makes it vulnerable may help us better understand how Loeys-Dietz syndrome progresses and, in that manner, how it can be slowed or prevented with treatments.”

Loeys-Dietz syndrome was identified in 2005 by then Johns Hopkins researcher Bart Loeys, M.D., Ph.D., and Hal Dietz, who directs Johns Hopkins’ research on Marfan syndrome, a genetic disorder similar to Loeys-Dietz syndrome. Marfan syndrome’s features were systematically described by the late Victor McKusick, M.D., recognized as a father of human genetics as a medical discipline.

Loeys-Dietz syndrome is estimated to affect one in 50,000 people, according to a report by Loeys and Dietz. One of the classes of medications available to treat people with Loeys-Dietz syndrome is angiotensin II receptor blockers (ARBs), which are more generally used to treat high blood pressure. The medicines suppress progression of aneurysms in mouse models and people with Marfan syndrome, potentially reducing the risk of vascular tears, early death or the need for surgery.

“The new findings could help us better understand why the aortic root is likely to dilate in patients with Loeys-Dietz syndrome,” says Dietz. “Our research could eventually help refine treatment strategies for this condition, and potentially other vascular connective tissue disorders.”

To begin the current study, Emily Bramel, Ph.D., now a postdoctoral fellow at the Broad Institute in Boston, analyzed mice that were genetically engineered to show the features of Loeys-Dietz syndrome, including aortic root aneurysm. Bramel, who worked in MacFarlane’s lab while a Johns Hopkins graduate student, compared her findings in mouse models with data obtained from analysis of aortic cells collected with permission from people with Loeys-Dietz syndrome. The data were shared by Stanford University cardiac surgeons Albert Pedroza, M.D., Ph.D., and Michael Fischbein, M.D., Ph.D.

This comparison between aortic cells from people and mice was facilitated by a tool created by Johns Hopkins computational scientist Genevieve Stein-O’Brien, Ph.D., M.H.S., which compared gene expression patterns across tissues and species.

“We found that cells expressing high levels of Gata4 were present in higher numbers in the aortic root of mice and humans with Loeys-Dietz syndrome, begging the question of whether this contributes to the vulnerability for aneurysm formation,” MacFarlane says.

Smooth muscle cells with the Tgfbr1 mutation seem to be unable to properly degrade excess Gata4 protein, resulting in its accumulation, MacFarlane says. While Gata4 is necessary for many processes, the scientists say too much Gata4 can be harmful because it results in excess levels of the angiotensin II receptor — the molecule targeted by ARBs.

Because Gata4 is crucial to development of systems throughout the body, MacFarlane says it’s unlikely drugs could tinker safely with the protein directly. However, in future studies, the scientists hope to learn why the mutation that causes Loeys-Dietz syndrome leads to an accumulation of Gata4.  

“The process that triggers an excess of Gata4 could potentially be targeted by a drug,” MacFarlane says. “We just need to understand how it works.”

In addition to Bramel, MacFarlane, Dietz, Stein-O’Brien, Pedroza and Fischbein, scientists who contributed to this work are Johns Hopkins scientists Wendy Espinoza Camejo, Tyler Creamer, Leda Restrepo, Muzna Saqib, Rustam Bagirzadeh, Anthony Zeng and Jacob Mitchell.

The research was funded by the National Institutes of Health (S10OD023548, R01HL147947, F31HL163924), the Marfan Foundation, the Loeys-Dietz Syndrome Foundation and the Johns Hopkins Broccoli Center for Aortic Diseases.