Lindsey Lab
PROJECT 1: TARGETING GPER IN FEMALE CARDIOVASCULAR DISEASE
PROJECT 2: IDENTIFYING ALTERNATIVE TREATMENT REGIMENS FOR ESTROGEN
PROJECT 3: CHARACTERIZING NEW ESTROGEN RECEPTOR LIGANDS
PROJECT 4: ENVIRONMENTAL ESTROGENS IN FEMALE CARDIOVASCULAR HEALTH
PUBLICATIONS
TULANE CENTER OF EXCELLENCE
SEX-BASED BIOLOGY & MEDICINE
PROJECT 1: TARGETING GPER IN FEMALE CARDIOVASCULAR DISEASE
Estrogen receptors (ER) α and β are classical steroid receptors that use genomic signaling to mediate the reproductive effects of this sex hormone. However, work by our lab and others show that acute signaling via the newly discovered G protein-coupled estrogen receptor (GPER) contributes significantly to estrogen’s cardioprotective effects. Our previous results show that in vivo administration of the selective GPER agonist G-1 significantly reduces blood pressure in and alters vascular expression and function of the renin-angiotensin system. We also found that GPER significantly attenuates renal damage and oxidative stress and induces vasorelaxation which is reduced during aging. Therefore, a reduction in GPER signaling may be one factor that underlies adverse effects of postmenopausal hormone therapy. This project will elucidate the contribution of GPER to vascular and renal health and will determine whether hormone therapies that preferentially bind this receptor may be a potential way to avoid the adverse effects experienced during hormone therapy.
PROJECT 2: IDENTIFYING ALTERNATIVE TREATMENT REGIMENS FOR ESTROGEN
Current recommendations are to limit the use of hormone therapy for the treatment of menopausal symptoms to a few years because the potential health risks associated with exposure to estrogens preclude their long-term use. Interestingly, short-term exposure to estrogens during a “critical window” after the loss of ovarian function provides long-lasting benefits. For example, in women who received 2-3 years of hormone therapy in the early menopausal years, the risk for cognitive impairment and cardiovascular disease is decreased 5-15 years later. Therefore, midlife estrogen use may have lasting effects.
Preliminary data collected in the Lindsey lab shows that both short- and long-term E2 lowers systolic blood pressure in the same animal model. Surprisingly, however, long-term E2 was detrimental for tissue hypertrophy and renal damage. These experiments provide an excellent framework for establishing the relationship between cardiovascular disease and duration of hormone therapy. The data obtained through this collaborative work will hopefully alleviate the current controversy on whether midlife estrogen exposure exerts beneficial actions on cardiovascular diseases later in life.
PROJECT 3: CHARACTERIZING NEW ESTROGEN RECEPTOR LIGANDS
Our laboratory was the first to demonstrate that GPER plays a role in the antihypertensive effects of estrogen. Activation of GPER alone dilates resistance arteries to the same extent as nonselective estrogen receptor activation with 17-β-estradiol. Our findings indicate that GPER mediates the beneficial cardiovascular actions of estrogen. The translation of our research to pharmaceutical interventions will be greatly enhanced by assessing the compounds that are currently prescribed to postmenopausal women, namely Premarin, both alone and in combination with bazedoxifene (Duavee). In comparison to 17-β-estradiol, the combination of equine estrogens found in Premarin may produce less than optimal effects in the aging female cardiovascular system. However, selective estrogen receptor modulators such as tamoxifen and raloxifene, the chemical predecessor of bazedoxifene, elicit beneficial estrogenic actions in various tissues via activation of GPER. Therefore, combining Premarin with bazedoxifene presents a novel pharmaceutical strategy for shifting the balance of estrogen receptor activation towards GPER and eliciting well-characterized cardiovascular benefits.
PROJECT 4: ENVIRONMENTAL ESTROGENS IN FEMALE CARDIOVASCULAR HEALTH
Women are exposed to exogenous estrogens throughout their lifetime that impact the cardiovascular system. The effects of these exogenous estrogens become even more relevant in the later stages of life when endogenous estrogens are low. We postulate that exogenous estrogens such as bisphenol A (BPA) are detrimental to female cardiovascular health by promoting hypertension and that lifetime exposure should be reduced. his study is highly significant because it will assess the effects of a ubiquitous nontraditional estrogen on a cardiovascular health problem that negatively impacts individuals and society. Bisphenol A (BPA) is an industrial chemical that promotes cancer in the reproductive tract, breast , and prostate and induces reproductive and developmental abnormalities. However, no studies to date have considered how exogenous estrogens impact the female cardiovascular system. Many of these estrogens, including BPA, have significant binding affinity for the novel estrogen receptor GPER, but we do not know whether it impacts its cardiovascular effects.
