The Role of Thromboxane A2 in Vascular Regulation in Women with Endometriosis

血栓素 A2 在子宫内膜异位症女性血管调节中的作用

• 批准号: 10750782
• 负责人: Auni Williams
• 金额: $ 4.7万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750782
• 关键词: Acceleration; Affect; Atherosclerosis; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Development; Diffuse; Endothelial Cells; Endothelium; Enzymes; Event; Exercise; Gynecologic; Impairment; Inflammation; Lesion; Mediating; Nitric Oxide; Nitric Oxide Synthase; Pain; Patients; Physiological; Play; Population; Pre-Clinical Model; Reflex action; Regulation; Research; Risk Factors; Role; Sensory; Skeletal Muscle; Stimulus; Thromboxane A2; Training; Translating; Uterus; Vascular Smooth Muscle; Vasoconstrictor Agents; Vasodilation; Vasomotor; Woman; antagonist; cardiovascular disorder risk; chronic pain; cyclooxygenase 2; endometriosis; endothelial dysfunction; pharmacologic; pre-doctoral; prevent; preventive intervention; receptor; systemic inflammatory response; vasoconstriction

Project Summary CVD is the leading cause of death worldwide. Endometriosis has been repeatedly identified as an independent risk factor for CVD that affects an estimated one in ten women in the world. Endometriosis is a gynecologic condition characterized by invasive extrauterine endometriotic lesions, chronic pain and pain sensitization, and systemic inflammation and is associated with accelerated cardiovascular disease risk. The expression of cyclooxygenase-2, a key enzyme in inflammation, is upregulated in endometriotic lesions as are its metabolites, namely TxA2. TxA2 is a potent vasoconstrictor able to diffuse across the endothelium to act directly on its receptors in the vascular smooth muscle. TxA2 can also antagonize NOS within the endothelial cells, preventing vasodilation. A decrease in nitric oxide (NO)-mediated vasodilation defines endothelial dysfunction and is regarded as a critical early event in the development of atherosclerosis and overt cardiovascular disease. Women with endometriosis demonstrate marked endothelial dysfunction compared with healthy controls. Furthermore, TxA2 receptors (TP) play a key role in sensitizing the sensory afferents in skeletal muscle in pre- clinical models of cardiovascular disease, leading to an exaggerated exercise pressor reflex. This is a strong predictor of major adverse cardiovascular events in cardiovascular disease patients. Therefore, the purpose of this project is twofold: 1) to determine the effect of the TP on the regulation of microvascular function and in circulating platelets in women with endometriosis and 2) to investigate sensory afferent sensitization in women with endometriosis. We hypothesize that women with endometriosis demonstrate exaggerated vasoconstriction to both pharmacological stimuli locally modulating vasomotor tone and to physiological sympathoexcitatory stimuli. This project and associated training plan will serve as a vehicle for exceptional predoctoral training for the candidate.

项目摘要 CVD是全球死亡的主要原因。子宫内膜异位症已被反复确定为一个独立的 心血管疾病的危险因素，影响估计十分之一的妇女在世界上。子宫内膜异位症是一种 以侵入性子宫外增生性病变、慢性疼痛和疼痛致敏为特征的病症，以及 全身性炎症，并与加速心血管疾病风险相关。的表达 环氧合酶-2是炎症中的关键酶，其代谢产物在炎症病变中上调， 即TxA 2。TxA 2是一种有效的血管收缩剂，能够扩散穿过内皮，直接作用于其血管内皮细胞。 血管平滑肌中的受体。TxA 2还可以拮抗内皮细胞内的NOS，防止内皮细胞的凋亡。 血管舒张一氧化氮（NO）介导的血管舒张的减少定义了内皮功能障碍， 被认为是动脉粥样硬化和明显心血管疾病发展的关键早期事件。 与健康对照组相比，子宫内膜异位症患者表现出明显的内皮功能障碍。 此外，TxA 2受体（TP）在预处理骨骼肌感觉传入的增敏中起关键作用。 心血管疾病的临床模型，导致过度的运动升压反射。这是一个强烈 心血管疾病患者主要不良心血管事件的预测因子。因此， 本项目包括两个方面：1）确定TP对微血管功能的调节作用， 子宫内膜异位症妇女的循环血小板和2）调查妇女的感觉传入敏化 子宫内膜异位症我们假设子宫内膜异位症的妇女表现出过度的血管收缩 局部调节血管紧张性的药理学刺激和生理性交感神经兴奋 刺激。这个项目和相关的培训计划将作为一个特殊的博士前培训的工具， 候选人。