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

子宫内膜异位症是一种衰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6-10%的女性患有子宫内膜异位症 并患有包括慢性盆腔疼痛、性交疼痛、不孕症和其他并发症在内的症状， 与全身炎症相关的疾病。这种疾病的广泛传播性质延伸到影响 总体健康状况，包括导致心血管疾病（CVD）风险升高-心血管疾病的主要原因 女人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，暴露对女性有益，但子宫内膜异位症的治疗标准 包括雌激素抑制。这为长期管理女性心血管疾病风险带来了难题 子宫内膜异位症这一提议填补了先前对炎症信号作用的研究中的一个重大空白， CVD风险和有效干预措施，以减轻心血管合并症。循环氧化脂质和 子宫内膜异位症妇女中升高的炎性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）导致显著的内皮损伤， 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，因此子宫内膜异位症治疗的护理标准可能 加重心血管疾病风险。我们的工作模型是，糖尿病相关的全身炎症介质 增加LOX-1受体活性并导致内皮功能障碍。我们的假设是， 子宫内膜异位症增加的CVD风险是慢性全身性炎症诱导内皮细胞增殖的结果。 功能障碍，通过LOX-1受体介导，这种CVD风险被标准雌激素加重 抑制治疗。在本申请中，我们使用多管齐下的方法，包括在体内和离体人， 生理实验，以确定炎症和雌激素抑制对心血管疾病的作用， 子宫内膜异位症的具体结果。这一系列的研究在妇女子宫内膜异位症将 描述雌二醇（特定目标1）和全身炎症（特定目标2）在子宫内膜异位症中的作用- 加速CVD风险。这些研究将评估新的信号机制，包括连接 通过下游普遍存在的清道夫受体的激活，这是CVD和子宫内膜异位症的共同点 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，包括选择性雌激素 受体调节剂巴多昔芬和他汀类辛伐他汀在减轻子宫内膜异位症妇女心血管疾病风险中的作用。 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 子宫内膜异位症妇女的CVD负担。

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.