This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The decline in circulating plasma estrogen (17beta-estradiol) after menopause is associated with a dramatic increase in the incidence of cardiovascular disease, the leading cause of death for women in the US. In particular, the drop in plasma estrogen is a risk factor for the development of hypertension, suggesting that the gonadal production of estrogen is protective against elevation in blood pressure. The long-term goal of this project is to uncover the cellular mechanisms associated with menopause-induced hypertension. This will provide additional evidence on how circulating estrogen protects against abnormal vascular tone and high blood pressure. One of the cellular mechanisms implicated in the development of hypertension is an overexpression of voltage-gated (L-type) calcium channels (CaV channels) that results in excessive Ca2+ influx, which in turn leads to vasoconstriction of small arteries and arterioles. Although there are no reported studies linking CaV channel expression with plasma estrogen levels, our preliminary work indicates that estrogen decreases CaV channel expression in the vasculature. Moreover, some studies suggest that in vivo estrogen deficiency induces an increased Ca2+ influx through CaV channels. This project will use an ovariectomized (OVX) knockout (KO) mouse model devoid of the CaV beta3 subunit to test the hypothesis that estrogen suppresses CaV channel expression by preventing the association of the ancillary beta3 subunit with the pore-forming alpha 1C subunit of the CaV channel. We further predict that estrogen deficiency (due to ovariectomy) will induce the association of the beta3 and alpha 1C subunits and lead to CaV channel expression on the cell surface. These hypotheses clearly fit into the AR INBRE theme of """"""""cell signaling, growth, and differentiation. Determining the mechanism(s) by which estrogen loss contributes to cardiovascular disease could result in a therapeutic strategy for postmenopausal women that would limit alpha1C expression, and thereby ameliorate excessive CaV channel expression and reduce vasoconstriction.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRR1-RI-7 (01))
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University of Arkansas for Medical Sciences
Schools of Medicine
Little Rock
United States
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