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

摘要（家长补助金） 子宫内膜异位症是一种虚弱的雌激素依赖性妇科疾病， 子宫腔外的子宫内膜样组织。大约有6-10%的女性 子宫内膜异位症和遭受的症状，包括慢性盆腔疼痛，疼痛在性交， 不孕症和其他与全身炎症相关的并发症。的广泛性 这种疾病扩展到影响整体健康，包括导致心血管疾病的风险增加， 心血管疾病（CVD）-妇女死亡的主要原因。子宫内膜异位症和动脉粥样硬化性心血管疾病是 都是炎症引起的疾病从心血管疾病的角度来看，雌激素暴露对女性有益， 但子宫内膜异位症的标准治疗包括雌激素抑制。这将创建一个 子宫内膜异位症女性CVD风险长期管理的难题该提案填补了 在先前的研究中，炎症信号的作用，CVD风险和有效的 减轻心血管合并症的干预措施。循环氧化脂质和炎症 子宫内膜异位症妇女中升高的细胞因子刺激了子宫内膜异位症患者普遍表达的 血管系统上的清道夫凝集素样氧化LDL受体（LOX-1）导致显著的 血管内皮功能障碍是CVD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，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。我们的工作模式是， 炎症介质增加LOX-1受体活性并导致内皮功能障碍。我们的全球 假设子宫内膜异位症妇女心血管疾病风险增加是由于慢性全身性 炎症诱导内皮功能障碍，通过LOX-1受体介导，这种CVD风险是 标准的雌激素抑制治疗会加重病情在这个应用程序中，我们使用一个多管齐下的 方法包括体内和离体人体生理实验，以确定的作用， 炎症和雌激素抑制对心血管特异性结局的影响 子宫内膜异位症这一系列的研究，妇女子宫内膜异位症将描绘的作用，雌二醇 （具体目标1）和全身性炎症（具体目标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机制，包括共同的联系， CVD和子宫内膜异位症通过下游激活普遍存在的清道夫受体 LOX-1。我们还将测试两种不同的干预措施（具体目标3）的效果，包括选择性干预。 雌激素受体调节剂巴多昔芬和他汀类辛伐他汀降低女性心血管疾病风险 子宫内膜异位症我们的研究有可能确定临床相关的治疗靶点， 干预，从而降低子宫内膜异位症妇女的CVD负担。

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.