Estrogen as a Regulator of the Sphingolipid Balance in the Human Microcirculation

摘要 微血管内皮功能障碍可预测未来的主要不良心脏事件（MACE）。鞘脂， 具有生物活性的脂质是内皮功能的有效调节剂，并且还防止或促进内皮细胞的生长。 心脏病的发展。拟议的研究是目前项目的扩展，该项目使用一种独特的 和翻译的方法来检查鞘脂代谢对流动诱导的介质的影响， 血管舒张（FID）在人体微血管内。小动脉暴露于神经酰胺，一种鞘脂， 血浆中的升高是MACE的独立危险因素，通过产生H2 O2对血流作出反应而扩张， 炎症和促动脉粥样硬化介质，而不是一氧化氮（NO），抗炎，抗- 健康成人使用的动脉粥样硬化介质。相反，鞘氨醇-1-磷酸（S1 P），也在 鞘脂家族和神经酰胺的代谢物，恢复了患有 冠状动脉疾病（CAD）。雌激素是已知的鞘脂平衡调节剂，有趣的是， 刺激S1 P或神经酰胺产生。雌激素诱导的S1 P形成可以解释其在前 绝经期妇女，而雌激素补充剂可能会在微血管中向神经酰胺倾斜 从而增加患心血管疾病的风险。提出的两个目标扩展了目前的工作 通过研究雌激素（生理和升高）对人微血管中FID介质的影响， 无论是年轻的还是年长的女性初步数据表明，性别特异性差异也被观察到 与雌激素有关，因此可能对跨性别女性群体有影响。S1 P：神经酰胺比例 对生理水平和升高水平的雌激素治疗的反应将在性别特异性 内皮细胞这些研究属于受资助的父母补助金的范围，将为以下方面提供宝贵的见解： 如何损失的雌激素在过渡到更年期，以及如何升高量的雌激素（如口服 避孕药，激素治疗），增加未来心血管疾病的风险。由此产生的数据 这项提案将增加对雌激素在微血管中的积极和消极作用的关键机制的见解， 在整个生命周期中，顺性别女性以及跨性别女性群体都是如此。

ABSTRACT Microvascular endothelial dysfunction predicts future major adverse cardiac events (MACE). Sphingolipids, biologically active lipids, are potent regulators of endothelial function and also prevent or promote the development of heart disease. The studies proposed are an expansion of the current project which uses a unique and translational approach to examine the effects of sphingolipid metabolism on the mediator of flow-induced vasodilation (FID) within the human microvasculature. Arterioles exposed to ceramide, a sphingolipid that when elevated in plasma is an independent risk factor for MACE, dilate in response to flow by generating H2O2, a pro- inflammatory and pro- atherosclerotic mediator as opposed to nitric oxide (NO), the anti-inflammatory, anti- atherosclerotic mediator utilized by healthy adults. On the contrary, sphingosine-1-phosphate (S1P), also within the sphingolipid family and a metabolite of ceramide, restores NO-dependent FID in arterioles from patients with coronary artery disease (CAD). Estrogen is a known regulator of the sphingolipid balance and interestingly can stimulate production of S1P or ceramide. Estrogen-induced S1P formation may explain its protective role in pre- menopausal women, whereas estrogen supplementation may tip the balance towards ceramide in microvessels from older women thus increasing cardiovascular disease risk. The two aims proposed extend the current work by investigating the effect of estrogen (physiological and elevated) on the mediator of FID in human microvessels from both young and older females. Preliminary data suggest that sex-specific differences are also observed with estrogen and therefore may have implications for the trans-female population. The S1P:ceramide ratio in response to both physiological and elevated levels of estrogen treatment will be measured in sex-specific endothelial cells. These studies are in the scope of the funded parent grant and will offer valuable insight into how loss of estrogen during the transition to menopause, as well as how elevated amounts of estrogen (e.g. oral contraceptives, hormone therapy), increases future cardiovascular disease risk. Data generated from this proposal will add critical mechanistic insight into the positive and negative microvascular effects of estrogen in both cis-gender females throughout the lifespan as well as the trans-female population.