Sphingolipid signaling in age-associated vascular pathology

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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.