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衰弱的雌激素依赖型妇科疾病，源于 子宫腔外部位的子宫内膜样组织。大约6%-10%的女性患有子宫内膜异位症 并出现慢性盆腔疼痛、性交疼痛、不孕不育等症状。 与全身炎症相关的病态。这种疾病的广泛性延伸到了影响 总体健康，包括增加心血管疾病(CVD)的风险--这是 女性的死亡。子宫内膜异位症和动脉粥样硬化性心血管疾病都是由炎症引起的疾病。雌激素 从心血管疾病的角度来看，暴露对女性是有益的，但治疗子宫内膜异位症的标准是 包括雌激素抑制。这给女性心血管疾病风险的长期管理带来了难题。 患有子宫内膜异位症。这一提议填补了先前关于炎症信号作用的研究的一个重大空白， 心血管疾病的风险和有效的干预措施，以减轻心血管并发症。循环氧化脂质和 子宫内膜异位症患者体内炎性细胞因子的升高刺激其普遍表达 清除剂凝集素样氧化低密度脂蛋白受体(LOX-1)在血管系统上的表达，导致明显的内皮细胞 功能障碍，这是心血管疾病风险增加的最早可检测指标之一。雌激素直接抑制LOX-1- 依赖性内皮功能障碍，因此治疗子宫内膜异位症的护理标准可能是 加剧了心血管疾病的风险。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 增加LOX-1受体活性，导致内皮功能障碍。我们的全球假设是，在女性 随着子宫内膜异位症心血管风险的增加，慢性全身炎症诱导内皮细胞生长 通过LOX-1受体介导的功能障碍，这种心血管疾病的风险被标准雌激素加剧 抑制疗法。在这项应用中，我们使用了包括体内和体外人类在内的多管齐下的方法 确定炎症和雌激素抑制对心血管的作用的生理学实验 子宫内膜异位症的特殊结局。这一系列针对患有子宫内膜异位症的女性的研究将 描述雌激素(特异性目标1)和全身性炎症(特异性目标2)在子宫内膜异位症中的作用 相关的加速心血管疾病风险。这些研究将评估新的信号机制，包括连锁 通过无处不在的清道夫受体的下游激活而共同发生于心血管疾病和子宫内膜异位症 LOX-1。我们还将测试两种截然不同的干预措施(具体目标3)的效果，包括选择性雌激素。 受体调节剂巴多昔芬和他汀类药物辛伐他汀在降低子宫内膜异位症患者心血管风险中的作用。 我们的研究有可能确定临床相关的治疗靶点和干预措施，从而减少 子宫内膜异位症患者的心血管负担。