Sphingolipid signaling in age-associated vascular pathology

摘要 与年龄相关的血管功能下降是器官功能下降的关键因素， 活力、对压力的抵抗力和更高的发病率/死亡率。我们的实验室已经制造出 关于脂类介体(鞘磷脂和前列腺素)如何增强的长期贡献 血管内皮细胞(EC)的功能和对病理过程的弹性。我们最近 数据表明，EC保护性1-磷酸鞘氨醇(S1P)的年龄相关性下降 信号转导参与了多种器官的EC功能障碍和病理改变。具体地说，循环 通过EC S1P受体-1(S1PR1)的高密度脂蛋白结合的S1P信号是增强 EC Resilience和旨在对抗其年龄依赖性下降的治疗策略是 对减轻脏器病变有效。这一前提得到了公正研究的进一步支持。 在载脂蛋白随年龄增长而减少的人群中，高密度脂蛋白上的S1P伴侣。我们 假设衰老损害了增强EC的血管保护S1P途径 韧性，从而导致器官功能迅速下降。这一假设的推论是 基于机制的EC S1PR1通路治疗增强将降低其发生率 器官特异性EC的下降。为了了解器官特有的血管衰老机制，我们 从新鲜分离的EC全球范围内分析转录组和染色质调节位点 正常小鼠的主动脉、肺和视网膜。这些器官中的EC缺陷会导致动脉粥样硬化， 中枢神经系统(CNS)对病毒感染和血管病理的抵抗力降低， 分别进行了分析。首先，我们将描述衰老诱导的主动脉内皮细胞-2(AEC2)。 S1PR1信号减弱，同时表现出炎症和纤维化基因的人群 签名。我们将定义AEC2细胞的年龄相关染色质调节因子，并评估 S1PR1/GI偏向信号对抗老年人这种病理性EC表型改变的能力 老鼠。第二，我们将验证肺EC(LEC)中EC S1PR1信号支持的假设 对病毒感染的抵抗力。衰老减弱LEC S1PR1信号的机制 将会被澄清。模拟高密度脂蛋白-S1P抑制病理变化的治疗策略 表型将进行测试。第三，用视网膜上皮细胞(REC)作为中枢神经系统的模型 血管系统，我们将检查S1PR1信号是否可以对抗与年龄相关的屏障破坏， 转运蛋白基因表达与星形胶质细胞增生症 信号激活器。这些研究有望带来新的见解，即 在衰老过程中，介质会导致血管功能障碍和疾病，这最终可能 导致新的治疗策略，以对抗与年龄相关的器官功能障碍和衰退。

SUMMARY Age-related decline in vascular function is a key factor in decreased organ function, vitality, resistance to stress and increased morbidity/ mortality. Our laboratory has made long-standing contributions about how lipid mediators (sphingolipids and prostanoids) enhance vascular endothelial cells (EC) function and resilience to pathological processes. Our recent data suggest that age-dependent decline in EC protective sphingosine 1-phosphate (S1P) signaling contributes to EC dysfunction and pathology of various organs. Specifically, circulatory HDL-bound S1P signaling via EC S1P receptor-1 (S1PR1) is a key mechanism that enhances EC resilience and that therapeutic strategies designed to counter its age-dependent decline was efficacious in reducing organ pathology. This premise is further supported by unbiased studies in humans which show age-dependent decrease in ApoM, the S1P chaperone on HDL. We hypothesize that aging compromises vasculoprotective S1P pathway which enhances EC resilience, thus contributing to rapid decline in organ function. The corollary of the hypothesis is that mechanism-based therapeutic enhancement of EC S1PR1 pathway will decrease the rate of decline of organ-specific EC. To understand organ-specific vascular aging mechanisms, we profiled the transcriptome and chromatin regulatory sites globally from freshly isolated EC from normal mouse aorta, lung and retina. EC defects in these organs lead to atherosclerosis, reduced resistance to viral infections and vascular pathology in central nervous system (CNS), respectively. First, we will characterize an aging-induced aortic endothelial cell-2 (AEC2) population which has attenuated S1PR1 signal while exhibiting inflammatory and fibrotic gene signature. We will define age-associated chromatin regulators of AEC2 cells and assess the ability of S1PR1/ Gi-biased signals to counteract this pathological EC phenotype change in aged mice. Second, we will test the hypothesis that EC S1PR1 signaling in lung EC (LEC) supports resilience against viral infections. Mechanisms by which aging attenuates LEC S1PR1 signaling will be elucidated. Therapeutic strategies that mimic HDL-S1P that suppress pathological phenotypes will be tested. Third, using the retinal EC (REC) as a model of the CNS vasculature, we will examine whether S1PR1 signal can counter age-related barrier breach, transporter gene expression and astrogliosis either alone or in combination with the Wnt signaling activators. These studies are anticipated to lead to new insights by which lipid mediators contribute to vascular dysfunction and disease during aging, which could ultimately lead to novel therapeutic strategies to combat age-related organ dysfunction and decline.