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：
10340678
负责人：
Lacy M. ALEXANDER
金额：
$ 78.41万
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/10340678
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 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，是一种使雌激素依赖性的妇科疾病造成的使人衰弱的人子宫内膜在子宫腔外的部位。大约6-10％的女性患有子宫内膜异位症并患有症状，包括慢性骨盆疼痛，性交期间的疼痛，不育症和其他共同与全身性炎症有关的病态。该疾病的广泛性质扩展到影响总体健康，包括导致心血管疾病风险升高（CVD）的主要原因，这是女性死亡。子宫内膜异位症和动脉粥样硬化CVD都是炎症引起的疾病。雌激素从CVD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抑制雌激素。这为女性CVD风险的长期管理创造了一个难题与子宫内膜异位症。该提案填补了先前研究炎症信号传导作用的显着空白， CVD风险和有效的干预措施减轻心血管合并症。循环氧化的脂质和子宫内膜异位症女性升高的炎性细胞因子刺激无处不在的表达脉管系统上的清道夫凝集素样氧化的LDL受体（LOX-1），导致内皮明显功能障碍是CVD风险增加的最早可检测指标之一。雌激素直接抑制Lox-1- 依赖的内皮功能障碍，因此子宫内膜异位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性炎症介质增加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的CVD风险是导致慢性全身性炎症引起内皮的结果功能障碍，通过LOX-1受体介导，这种CVD风险因标准雌激素而加剧抑制治疗。在此应用程序中，我们使用一种多收益的方法，包括体内和体内人类生理实验，以确定炎症和雌激素抑制在心血管中的作用子宫内膜异位症的特定结果。对子宫内膜异位症女性的这一系列研究将描述雌二醇（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，包括联系通过无处不在的清道夫受体的下游激活CVD和子宫内膜异位症共有 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和他汀类药物辛伐他汀在减轻子宫内膜异位症女性的CVD风险中。我们的研究有可能识别临床相关的治疗靶标和干预措施，从而减少子宫内膜异位症女性的CVD负担。