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

摘要 微血管内皮细胞功能障碍可预测未来的主要不良心脏事件(MACE)。神经鞘脂类， 生物活性脂类是血管内皮细胞功能的有力调节者，也可以预防或促进 心脏病的发展。建议的研究是对目前项目的扩展，该项目使用了一种独特的 和翻译方法研究鞘磷脂代谢对流动诱导的介质的影响 人体微血管内的血管扩张(FID)。小动脉暴露于神经酰胺，一种鞘磷脂，当 血浆升高是MACE的独立危险因素，MACE通过产生过氧化氢而扩张，这是一种促进 炎症和促动脉粥样硬化介质与一氧化氮(NO)相反，一氧化氮(NO)是抗炎、抗动脉粥样硬化的 健康成年人使用的动脉粥样硬化介体。相反，鞘氨醇-1-磷酸(S1P)，也在 鞘磷脂家族是神经酰胺的代谢物，可以恢复慢性阻塞性肺疾病患者小动脉中NO依赖的FID。 冠状动脉疾病。雌激素是鞘磷脂平衡的已知调节者，有趣的是，雌激素可以 刺激S1P或神经酰胺的产生。雌激素诱导的S1P的形成可能解释了其在Pre-Pre中的保护作用 更年期女性，而补充雌激素可能会使微血管中的平衡向神经酰胺倾斜 因此增加了患心血管疾病的风险。这两个目标的提出是对当前工作的延伸 通过研究雌激素(生理和升高)对人微血管FID介质的影响 无论是年轻的还是年长的雌性。初步数据表明，还观察到了性别差异。 与雌激素有关，因此可能会对跨女性人群产生影响。S1P：神经酰胺的比值 对生理和高水平雌激素治疗的反应将根据性别进行测量。 内皮细胞。这些研究都在家长资助的范围内，并将提供有价值的见解 如何在更年期过渡期间丢失雌激素，以及如何增加雌激素(例如口服 避孕药、激素疗法)，会增加未来患心血管疾病的风险。由此生成的数据 该提案将增加对雌激素积极和消极微血管效应的关键机制洞察力 无论是整个生命周期的顺性女性还是跨女性人口。

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.