A new study from UC San Francisco shows how certain cells in the brain may cause aneurysms to weaken and rupture. It helps explain why some aneurysms burst while others do not and could lead to new ways of predicting and possibly preventing strokes.
Brain aneurysms are bulges in blood vessels that can go unnoticed for years. If they rupture, they can cause a severe and often deadly type of stroke. About 1 in 50 Americans has a brain aneurysm, but doctors still struggle to predict which ones are most dangerous.
The new study helps to unpack the biology behind these events by mapping the cells in artery walls and the interactions that weaken them.
“We’ve made major steps toward solving the mystery of how aneurysms form,” said Ethan Winkler, MD, PhD, assistant professor of Neurological Surgery and senior author of the study, which appears June 10 in Nature Neuroscience . “We’ve identified the cast of characters involved and seen which ones are implicated at different phases of disease.”
Aneurysms can be repaired with surgery and other minimally invasive procedures, but treatment decisions are largely based on the size of the aneurysm, its location, and patient-specific risk factors. Aneurysms that are less than 7 millimeters are usually monitored rather than repaired, even though this is not a very reliable way of predicting which ones will burst.
Usually three layers of cells, except ...
Analyzing more than 100,000 individual cells from human aneurysms and healthy brain arteries, the research team identified 19 distinct cell types and determined which genes were active in each. They also mapped how the cells were organized within the vessel wall.
Healthy arteries contain three layers: a thin inner lining, a thick layer of smooth muscle in the middle that allows arteries to expand and contract with each heartbeat, and an outer layer of fibroblasts to provide structure.
In aneurysm tissue, those rings were disorganized and many of the smooth muscle cells had disappeared. In their place were scar-forming fibroblasts, which the team called “activated fibroblasts,” that stiffened the arterial wall and made it less able to flex as blood pulsed through. These cells expressed genes that have been linked to an inherited risk of aneurysm.
The researchers focused on a particular type of macrophage — which is an immune cell — that accumulated inside the arterial wall near the fibroblasts. To their surprise, the researchers discovered that these macrophages expressed a gene that is typically associated with bone tissue.
Further experiments revealed a destructive feedback loop between these two cell types. Activated fibroblasts released a signal that triggered these macrophages to produce enzymes that degrade the vessel’s structural support. When scientists blocked that signal, the macrophages were less likely to produce these enzymes.
Small aneurysm paradox explained
The study describes a process that gradually weakens the vessel walls. First, they lose supportive muscle cells, then stiff scar tissue builds up, activating inflammatory immune cells.
The findings help explain a clinical paradox: smaller aneurysms that are often considered low risk can still rupture. Winkler noted that more than half of the ruptures he treated early in his career occurred in aneurysms below the typical surgical threshold of 7 millimeters.
“We’ve had to rely on anatomy because we haven’t known the underlying biology,” he said.
A better understanding of how aneurysms form will create opportunities to intervene earlier — either by blocking the signals that fibroblasts send or by inhibiting the immune response to those signals.
“Maybe one day we’ll be able to stabilize an aneurysm to prevent it from bursting,” Winkler said. “That would be a very effective treatment — and one we’ve dreamed of for a long time.”
Authors: Other UCSF authors: Jerry C. Wang, Chang N. Kim, Shubhang Bhalla, Adnan Gopinadhan, Santhosh Arul, Damian Sanchez, Amanda C.M. Apolonio, Belda Gülsuyu, MD, Muhammet M. Öztürk, John Andrews, MD, Joseph Kim, PhD, Aunoy Poddar, Daniel L. Cooke, MD, Kazim Narsinh, MD, Eric J. Huang, MD, PhD, Edward F. Chang, MD, Daniel A. Lim, MD, PhD, Adib A. Abla, MD, Andrew C. Yang, PhD, Tomasz J. Nowakowski, PhD.
Funding: National Institute of Neurological Disorders and Stroke, National Institutes of Health (1F31NS147788, R01AG077780, R01NS123263, R01NS112357, R01NS124881, R2NS1125978, R01NS115815 and R21NS131689), the UCSF Discovery Fellowship, the California Institute for Regenerative Medicine (DISC0-14429), the U.S. Department of Veterans Affairs (I01BX000252), the Shurl and Kay Curci Foundation, the Marcus Program in Precision Medicine Innovation, the Cerebrovascular Section/Congress of Neurological Surgeons Foundation Young Investigator Research Award, the Barrow Neurological Foundation, the Brain Aneurysm Foundation, the Esther A. and Joseph Klingenstein Fund, the Sontag Foundation, the William K. Bowes Jr. Foundation, the Aneurysm and AVM Foundation, the Society of Neurointerventional Surgery, and the New York Stem Cell Foundation.
About UCSF: The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health , which serves as UCSF’s primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area. UCSF School of Medicine also has a regional campus in Fresno. Learn more at ucsf.edu or see our Fact Sheet .
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Nature Neuroscience