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Updated 10:00 AM October 25, 2004




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When gender matters:
Estrogen protects male rats from aortic aneurysms

When it comes to abdominal aortic aneurysms—life-threatening bulges or weak areas in the main artery feeding blood to the lower half of the body—new research shows that it definitely is better to be female.

During 2000, about 11,000 people in the United States died from a ruptured abdominal aortic aneurysm. Eighty percent of these aneurysms, which doctors call AAAs for short, occur in men. Scientists know little about why this often-undetected condition, for which there is no medical treatment, strikes men more often than women. But vascular surgeons at the Medical School have found some intriguing clues.
The results provide strong evidence for an estrogen-mediated
protective effect against the aneurysms.

At the American College of Surgeons (ACS) meeting in New Orleans earlier this month, Dr. Derek T. Woodrum, a resident in general surgery, presented new research results showing that smooth muscle cells from aortas of male rats contain 2.5 times more destructive MMP-9 protein and 10 times the level of MMP-9 gene expression compared to the same cells from female rat aortas. Known to be involved in AAA formation, MMP-9 is a cell-digesting enzyme that eats away at the wall of the aorta, leaving it vulnerable to expansion and rupture.

However, when Woodrum treated male rats with estradiol, a form of the female hormone estrogen, and then tested their aortas, he found that MMP-9 activity was substantially decreased. Woodrum received an ACS Excellence in Research Award for his study.

Woodrum conducted his research in the laboratory of Dr. Gilbert Upchurch, associate professor of surgery in the Medical School, who studies factors responsible for gender differences in abdominal aortic aneurysms.

"Earlier studies have demonstrated that increased estrogen systemically inhibits the development of AAAs," Upchurch says. "Dr. Woodrum's study extends earlier research and suggests that there also is something inherent in males that increases MMP-9 and may lead to greater AAA formation.

"Estrogen affects production of MMP-9 by white blood cells called macrophages," Upchurch adds. "MMPs degrade collagen and elastin, two major proteins in the aortic wall. Typically production of MMPs are part of the body's natural healing response to injury, but left unchecked, MMPs—in particular MMP-9—can cause extensive tissue damage and lead to the formation of an aneurysm."

In a recent paper published in Atheriosclerosis, Thrombosis and Vascular Biology (ATVB), Upchurch described a series of U-M experiments focused on gender differences in AAA formation and estrogen's protective effect. This study was one of the first to include both female and male experimental animals and to compare results between sexes.

The results provide strong evidence for an estrogen-mediated protective effect against the aneurysms, but Upchurch cautions that it does not mean everyone should start taking estrogen to protect against AAAs.

"There is no medical therapy for abdominal aortic aneurysms," he says. "But understanding exactly what triggers them and how they develop could lead to an effective therapy someday. It also could help us identify people with a high risk of AAA formation who need regular diagnostic testing."

The research was supported by the National Institutes of Health, the Jobst Vascular Research Fund, the Lifeline Foundation and U-M.

Dr. Gorav Ailawadi, a resident in surgery, was first author of the ATVB paper. Additional U-M collaborators included Dr. Jonathan L. Eliason, Dr. Karen J. Roelofs, Indranil Sinha, Kevin K. Hannawa, Dr. Eric P. Kaldjian, Dr. Guanyi Lu, Dr. Peter K. Henke, Dr. James C. Stanley, Dr. Stephen J. Weiss and Robert W. Thompson.

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