Mechanisms and interventions addressing accelerated cardiovascular disease risk in women with endometriosis

解决子宫内膜异位症女性心血管疾病风险加速的机制和干预措施

• 批准号: 10545738
• 负责人: Lacy M. ALEXANDER
• 金额: $ 76.68万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-05 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10545738
• 关键词: Acceleration; Address; Affect; Age; Atherosclerosis; Biological Markers; Blood Vessels; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Caring; Cause of Death; Chronic; Conjugated Estrogens; Disease; Endometrium; Endothelium; Estradiol; Estrogen Receptors; Estrogens; GNRH1 gene; Goals; Gonadotropin Hormone Releasing Hormone; Gonadotropin Releasing Hormone Inhibitor; Gynecologic; Health; Human; Impairment; Infertility; Inflammation; Inflammation Mediators; Inflammatory; Intervention; LOX gene; Lectin; Lipoprotein Receptor; Low-Density Lipoproteins; Measures; Mediating; Metabolism; Modeling; Nature; Nitric Oxide; Oral; Outcome; Oxidants; Pain; Peripheral; Physicians; Physiological; Physiology; Pre-Clinical Model; Process; Production; Proliferating; Receptor Activation; Reproductive Endocrinology; Research; Risk Factors; Role; Scientist; Selective Estrogen Receptor Modulators; Series; Signal Transduction; Simvastatin; Site; Symptoms; Syndrome; Testing; Therapeutic Intervention; Tissues; Uterine cavity; Vascular Diseases; Vasodilation; Woman; brachial artery; burden of illness; cardiovascular disorder risk; chronic pelvic pain; clinically relevant; comorbidity; cytokine; density; effective intervention; effectiveness measure; endometriosis; endothelial dysfunction; epidemiologic data; experience; experimental study; improved; in vivo; novel; oxidized LDL receptors; oxidized lipid; receptor; reduce symptoms; reproductive; salicylsalicylic acid; scavenger receptor; standard care; systemic inflammatory response; therapeutic target

Endometriosis and is a debilitating estrogen-dependent gynecological disorder deriving from the presence of endometrium like tissue in sites outside the uterine cavity. Approximately 6-10% of women have endometriosis and suffer from symptoms including chronic pelvic pain, pain during intercourse, infertility, and other co- morbidities associated with systemic inflammation. The widespread nature of this disease extends to impact overall health, including contributing to elevated risk of cardiovascular disease (CVD) --the leading cause of death in women. Endometriosis and atherosclerotic CVD are both inflammation-induced diseases. Estrogen exposure is beneficial for women from a CVD standpoint, but the standard of treatment for endometriosis includes estrogen suppression. This creates a conundrum for the long-term management of CVD risk in women with endometriosis. This proposal fills a significant gap in prior research into the role of inflammatory signaling, CVD risk and effective interventions to mitigate cardiovascular comorbidities. Circulating oxidized lipids and inflammatory cytokines that are elevated in women with endometriosis stimulate the ubiquitously expressed scavenger lectin-like oxidized LDL receptor (LOX-1) on the vasculature resulting in pronounced endothelial dysfunction, one of the earliest detectable indicators of increased CVD risk. Estrogen directly inhibits LOX-1- dependent endothelial dysfunction and thus the standards of care for endometriosis treatment may be exacerbating CVD risk. Our working model is that endometriosis-associated systemic inflammatory mediators increase LOX-1 receptor activity and result in endothelial dysfunction. Our global hypothesis is that in women with endometriosis increased CVD risk is the result chronic systemic inflammation inducing endothelial dysfunction, mediated through LOX-1 receptor, and this CVD risk is exacerbated by standard estrogen suppression treatments. In this application, we use a multipronged approach including in vivo and ex vivo human physiological experiments to determine the role of inflammation and estrogen suppression on cardiovascular specific outcomes in the setting of endometriosis. This series of studies in women with endometriosis will delineate the roles of estradiol (Specific Aim 1) and systemic inflammation (Specific Aim 2) in endometriosis- associated accelerated CVD risk. These studies will evaluate novel signaling mechanisms including the linkage common to both CVD and endometriosis through the downstream activation of the ubiquitous scavenger receptor LOX-1. We will also test the effects of two distinct interventions (Specific Aim 3) including the selective estrogen receptor modulator bazedoxifene, and the statin simvastatin in mitigating CVD risk in women with endometriosis. Our studies have the potential to identify clinically relevant therapeutic targets and interventions thus decreasing CVD burden in women with endometriosis.

子宫内膜异位症是一种使人衰弱的雌激素依赖的妇科疾病，由子宫内膜异位症引起