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 U-M research shows that it is definitely 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 very 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 University of Michigan Medical School have found some intriguing clues.
At this week's American College of Surgeons meeting in New Orleans, Derek T. Woodrum, M.D., a U-M resident in general surgery, will present 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. At this year's meeting, Woodrum will receive an American College of Surgeons “Excellence in Research Award” for his study.
Woodrum conducted his research in the laboratory of Gilbert Upchurch, M.D., an associate professor of surgery in the U-M 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 MMP's 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, 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 ATVB paper describes how scientists in the Upchurch laboratory first perfused the aortas of male and female rats with elastase, an enzyme that triggers an uncontrolled inflammatory reaction and creates an aneurysm in the aortic wall. Fourteen days later, 82 percent of the male rats, but only 29 percent of the female rats, showed evidence of AAA formation. Macrophages from male rats were shown to be responsible for the higher levels of the MMP-9 enzyme.
In a second group of experiments, U-M scientists surgically transplanted aortas from male to male rats, from female to male, and from female to female. After the rats were treated with elastase to stimulate aneurysm formation, scientists compared the effects on the transplanted aortas.