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: 10631533
• 负责人: Lacy M. ALEXANDER
• 金额: $ 1.67万
• 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: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10631533
• 关键词: 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; 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; Oxides; Pain; Peripheral; Physicians; Physiological; Physiology; Pre-Clinical Model; Process; Production; 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; oxidized low density lipoprotein; parent grant; receptor; reduce symptoms; reproductive; salicylsalicylic acid; scavenger receptor; standard care; systemic inflammatory response; therapeutic target

ABSTRACT (Parent Grant) Endometriosis 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 womenwith 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 estrogenreceptor 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.

摘要（父母赠款） 子宫内膜异位症是一种使人衰弱的雌激素依赖性妇科障碍 子宫内膜在子宫腔外的部位。大约6-10％的女性有 子宫内膜异位症和患有症状，包括慢性骨盆疼痛，性交期间的疼痛， 不育和与全身性炎症有关的其他共同病毒。广泛的本质 这种疾病扩展到影响整体健康，包括导致心血管风险升高 疾病（CVD） - 妇女死亡的主要原因。子宫内膜异位和动脉粥样硬化CVD是 两种炎症引起的疾病。从CVD的角度来看，雌激素暴露对女性有益， 但是子宫内膜异位症的治疗标准包括抑制雌激素。这会创建一个 难题，用于子宫内膜异位女性中CVD风险的长期管理。该建议填补了 先前研究炎症信号传导，CVD风险和有效作用的显着差距 减轻心血管合并症的干预措施。循环氧化脂质和炎症 子宫内膜异位症女性升高的细胞因子刺激无处不在表达的细胞因子 脉管系统上的清除型凝集素样氧化的LDL受体（LOX-1），导致明显 内皮功能障碍，这是CVD风险增加的最早检测指标之一。雌激素直接 抑制LOX-1-依赖性内皮功能障碍，从而抑制子宫内膜异位症的护理标准 治疗可能会加剧CVD风险。我们的工作模型是子宫内膜异位症相关的全身性 炎症介质会增加LOX-1受体活性，并导致内皮功能障碍。我们的全球 假设是，在子宫内膜异位症的女性中增加了CVD风险是慢性全身性的 通过LOX-1受体介导的炎症引起内皮功能障碍，该CVD风险为 通过标准的雌激素抑制处理加剧。在此应用程序中，我们使用多收益 方法包括体内和体内人类生理实验，以确定 在心血管特异性结果上的炎症和雌激素抑制 子宫内膜异位症。这一系列对子宫内膜异位女性的研究将描述雌二醇的作用 （特定目标1）和全身性炎症（特定目标2）在子宫内膜异位症相关的加速 CVD风险。这些研究将评估新的信号传导机制，包括 CVD和子宫内膜异位症都通过无处不在的清道夫受体的下游激活 LOX-1。我们还将测试两种不同的干预措施（特定目标3）的影响，包括选择性 雌激素受体调节剂Bazedoxifene，以及在缓解患有CVD的CVD风险中的他汀类药物的辛伐他法 子宫内膜异位症。我们的研究有可能识别临床相关的治疗靶标和 干预措施，减轻了子宫内膜异位症女性的CVD负担。