Abstract Dr. B. Hill
Title of Project Interaction of aging and estradiol metabolites on coronary arterial function
Abstract Atherosclerosis of the coronary arteries (i.e., coronary artery disease, CAD) is the number on killer of postmenopausal women and is considered an age-related disease. the protective effects of estradiol (i.e., estrogen) against CAD may be due to the action of its two primary metabolites, 2-hydroxyestradiol and 2-methoxyestradiol. the overall lone-term goal of this project is to understand how the metabolites of estradiol protect against age-induced changes of the coronary arteries and thereby prevent CA. These experiments will be conducted on the smooth muscle of coronary arteries from two different age groups, (9-month old verses 4 year old) of sexually mature female Yorkshire pigs. the overall hypothe4sis of this project is that 2-methoxyestradiol is more efficacious that 2-hydroxyestradiol in protecting against CAD by reducing arterial tone and decreasing the proliferation of smooth muscle cells. We predict that aging will eliminate these protective effects of the estradiol metabolites. the specific aims are to investigate the impact of aging, and 2-hydroxyestradiol and 2-methoxyestradiol on (1) the intracellular Ca2+ induced smooth muscle contraction, (2) the Ca2+ activated big potassium (BKCa) channel mediated arterial relaxation, and (3) smooth muscle cell proliferation. the methods for Aim 1 are to use fluorescent microscopy to measure intracellular Ca2+concentration ([Ca]i) changes in response to agonist-induced (K+ and endothelin-1, respectively) Ca2+ influx and Ca2+ release from the sarcoplasmic reticulum upon incubation of the smooth muscle cells in 2-hydroxyestradiol and 2-methoxyestradiol. then it will be determined if the [Ca]i changes produce changes in isometric contraction of arterial rings. Fro Aim # 2, whole cell patch clamp techniques will be used to measure BKCa channel current after exposing the isolated smooth muscle cells to 2-hydroxyestradiol or 2-methoxyestradiol. Next, the isometric relaxation of arterial rings will be investigated in response to 2-hydroxyestradiol or 2-methoxyestradiol in the presence of selective BKCa channel antagonists. Fro Aim #3, bromodeoxyuridine (BrdU) incorporation during the cell cycle will be used as a measure of DNA synthesis. A fluorescently tagged antibody to BrdU and FM will be used to measure BrdU incorporation into DNA. the overall relevance of this project is that the metabolites of estrogen may protect against CAD without causing estrogen-induced tumor growth.
Updated 07/31/2006
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