Estrogen, Aging and Vascular Inflammation

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DESCRIPTION (provided by applicant): Aging is characterized by systemic inflammatory changes and organ dysfunction. In females, loss of estrogen compounds these changes. Post-menopausal women have an abrupt acceleration of atherosclerosis. It would seem that restoration of estrogen would be protective; however, double- blind clinical studies on the use of estrogen replacement have not shown a benefit. Epoxyecosatrienoic acids (EETs), which are lipid signaling molecules, have important effects on angiogenesis, inflammation and are protective against ischemic injury. EETs represent the third pathway of arachidonic acid (AA) metabolism, in addition to prostaglandins and leukotrienes. Given their properties, EETs have the potential to be protective post-menopause. Soluble epoxide hydrolase (sEH) converts EETs to dihydroxy-eicosatrienoic acids (DHETs), which are thought to be pro- inflammatory and to lack the beneficial properties of EETs. In pilot studies we found that vascular sEH increased with aging and that left ventricular sEH expression decreased with estrogen replacement. Estrogen loss combined with aging leads to increased oxidative stress, increased inflammation, dysfunctional EPCs leading to impaired vascular repair, increased inflammation and increased monocyte adhesion. Our hypothesis is that EETs treatment and/or sEH inhibition, which will block hydrolysis of EETs to DHETs, can mitigate the inflammatory changes associated with estrogen loss and aging. We will address this hypothesis with three specific aims: SA 1 - Define the effect of aging vs. estrogen loss on EET metabolism, and the effect of changes in EET/DHETs on vascular function and inflammation. The planned work will investigate changes in EETs with aging and changes in estrogen status. End points will include the effect of EETs vs. estrogen on vascular function, regulation of EETs expression, and the metabolic profile of AA/EETs in aged and adult Norway Brown (NB) rats with and without estrogen. SA2 - Determine the effect of changes in EETs/DHETs vs. aging and E2 loss on EPCs function and proliferation. EETs have vasodilator, angiogenic and anti-inflammatory properties, but their effect on EPCs is not known. We hypothesize that aged EPCs will have impaired function, and that this will be improved by treatment with EETs. Endpoints in the planned work will include EPC proliferation, tube formation and both in vitro and in vivo models of homing and wound repair. SA3. - Investigate the effect of aging vs. estrogen withdrawal and EETs on monocyte activation and adhesion - These experiments explore the effect of aging vs. estrogen on monocyte activation, and how EETs/DHETs modify monocyte activation and adhesion. The planned studies will provide new knowledge of the effect of aging vs. estrogen loss, and the potential role of EETs in ameliorating the inflammatory changes of aging.