Irvine, Calif., October 23, 2001
A specific receptor for the sex hormone estrogen in the brain helps regulate pressure and blood flow there, a UC Irvine College of Medicine research team has found.
The receptor, which appears to influence certain genes' ability to produce nitric oxide and other chemicals that widen blood vessels, may be an effective target for new drugs to treat stroke and other injuries to the brain caused by high blood pressure. The researchers' study, conducted on mice, appears in the November issue of the Journal of Applied Physiology.
Sue Duckles, professor of pharmacology, and her colleagues found that the receptor, called alpha-ER, regulated estrogen's ability to dilate blood vessels in the brain by raising levels of nitric oxide and another known dilator called prostacyclin. By raising levels of nitric oxide and prostacyclin, estrogen could lower pressure in the brain's arteries.
"We believe this study is among the first to show how estrogen affects arteries in the cerebral cortex," Duckles said. "This receptor could help explain why women have fewer strokes than men before they reach menopause, and this knowledge may eventually lead to new treatments for stroke and other vascular disorders in the brain. Future research may expand our understanding of how blood pressure is regulated elsewhere in the body."
Blood pressure is a major risk factor in stroke and other cardiovascular disease. While the risk in women who have not reached menopause is lower than men, nearly 2 million women have a stroke each year. About 93,000 of them die of it, according to the National Heart, Lung and Blood Institute. In addition, about 10 percent of American women between the ages of 45 and 65 has heart disease; that proportion rises to 25 percent of women older than 65. Of women older than 65, about half have high blood pressure. Researchers suspect that a large reason for this rise is the diminishing levels of estrogen in older age.
Duckles and her colleagues found that estrogen treatment for one month resulted in elevated levels of nitric oxide synthase and cyclooxygenase-1, enzymes responsible for manufacturing the vasodilators, nitric oxide and prostacyclin. Mice who had been bred without the alpha-ER receptor were less able to dilate blood vessels when they were given estrogen. This led researchers to conclude that it was this receptor that controlled estrogen's actions on blood vessels in the brain.
Further, the receptor was located in the innermost layer of the blood vessel wall, known as the endothelium. From there, it controlled the manufacture of enzymes that produce chemicals that dilate or constrict the vessels.
"Estrogen appears to control how genes produce at least some of the enzymes that affect dilation and pressure in vessels in the brain," Duckles said. "While scientists knew that an estrogen receptor was at work, they didn't know which specific type played the most important role. By identifying alpha-ER, we have brought this work closer to eventually identifying possible drugs that work on the receptor to increase blood flow."
The researchers now are exploring other enzymes and genes that may be controlling dilation and blood pressure and conducting more tests to determine what chemicals may best control the alpha-estrogen receptor.
Duckles' colleagues in the study included Greg Geary, Anne Marie McNeill, Jose Ospina and Diana Krause of UCI, and Kenneth Korach of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C. The National Heart, Lung and Blood Institute supported the study.