The principal investigator proposes to test the hypothesis that estrogens act as protective agents against endothelial damage through the production of the growth factor, heparin-binding EGF (HB-EGF), which in turn stimulates the production of NO, the endothelium dependent relaxation factor. She will first determine whether the message levels for NO synthase III are increased after the treatment of human umbilical vein endothelial cells (HUVEC) with exogenous HB-EGF. A time course will be established for the stimulation of NOS III mRNA and NOS III protein. Next she will study whether estrogen treatment of the cells stimulates the production of both HB-EGF and NOS III mRNAs. If effects are found, then the effect of an estrogen antagonist will be studied to determine if estrogen is acting through its receptor. Using lyso PC as a model for 'oxidized lipid' the applicant will investigate whether chronic estrogen treatment will attenuate the stimulation of HB-EGF and NOS III by the oxidized lipids. The goal of the project is to determine if HB-EGF serves as as a diagnostic biomarker for dysfunctional endothelium, and if it plays a role in endothelium-dependent NO production by regulating expression of NOS III.
