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

基本信息

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
项目类别：
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

项目摘要

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性妇科疾病，源于子宫内膜异位症的存在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患有慢性盆腔疼痛、性交疼痛、不孕症和其他并发症等症状与全身炎症相关的发病率。这种疾病的广泛性影响到整体健康状况，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性死亡。子宫内膜异位症和动脉粥样硬化性CVD都是炎症引起的疾病。雌激素从心血管疾病的角度来看，暴露于女性是有益的，但子宫内膜异位症的治疗标准包括雌激素抑制。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。该提议填补了先前关于炎症信号传导作用的研究中的一个重大空白， CVD 风险和减轻心血管合并症的有效干预措施。循环氧化脂质和子宫内膜异位症女性体内炎症细胞因子升高，刺激普遍表达的炎症细胞因子血管系统上的清道夫凝集素样氧化 LDL 受体 (LOX-1) 导致明显的内皮细胞功能障碍，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是加剧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。我们的全球假设是，在女性中子宫内膜异位症增加CVD风险是诱发内皮细胞慢性全身炎症的结果通过 LOX-1 受体介导的功能障碍，标准雌激素会加剧这种 CVD 风险抑制治疗。在此应用中，我们使用多管齐下的方法，包括体内和离体人类确定炎症和雌激素抑制对心血管作用的生理实验子宫内膜异位症的具体结果。这一系列针对子宫内膜异位症女性的研究将描述雌二醇（具体目标 1）和全身炎症（具体目标 2）在子宫内膜异位症中的作用 - 相关的加速 CVD 风险。这些研究将评估新的信号传导机制，包括连接通过普遍存在的清道夫受体的下游激活，对于CVD和子宫内膜异位症来说是常见的 LOX-1。我们还将测试两种不同干预措施（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可降低子宫内膜异位症女性的 CVD 风险。我们的研究有可能确定临床相关的治疗目标和干预措施，从而减少子宫内膜异位症女性的 CVD 负担。