Sphingolipid signaling in age-associated vascular pathology

与年龄相关的血管功能下降是器官功能、活力、

Age-related decline in vascular function is a key factor in decreased organ function, vitality, resistance to stress and increased morbidity/ mortality from cardiovascular and inflammatory diseases. Our laboratory has made long-standing contributions in the areas of two lipid mediators – namely, sphingosine 1-phosphate (S1P) and prostacyclin (PGI2), which regulate vascular system and inflammatory processes. Our recent data suggest that age-dependent decline in S1P and PGI2 signaling axes contribute to vascular dysfunction and disease, thereby contributing to age-related functional decline in organs. Specifically, S1P signaling shifts from homeostatic to pro- inflammatory and injurious states during aging. Clinical studies show that attenuated S1P and PGI2 signaling axes contribute to increased incidence of cardiovascular disease. This proposal is based on the premise that that dysregulation of lipid mediator signaling pathways are important in age-related inflammatory and cardiovascular diseases that lead to significant functional decline, mortality and morbidity. The central hypothesis of the proposal is that decreased vasculoprotective S1P pathway in the endothelium contributes to age-associated vascular dysfunction and disease. Such age-associated processes affect the heterogenous vascular endothelium of aorta, retina and liver in a specific, mechanistically-tractable way to attenuate organ function. We aim to define the transcriptome of heterogenous endothelial cells from liver, retina and aorta of the mouse during aging. Similar analysis will also be done from aged mice in which S1PR1 signaling pathway in the endothelium is attenuated by genetic means. Second, we will define the mechanisms by which PGI2 signaling in the endothelium synergizes with the S1PR1 to enhance vasculoprotective signaling and promote vascular health. Third, we will elucidate the mechanisms by which age- dependent induction of S1PR2 antagonizes S1PR1 and induce vascular dysfunction and inflammation. Mouse genetic models as well as pharmacological inhibitors of S1PR2 will be tested to determine their utility in the treatment of age-related vascular dysfunction and disease. These studies are anticipated to lead to new insights by which lipid mediator signaling pathways contribute to age-dependent vascular dysfunction and disease, which could ultimately lead to novel therapeutic strategies to combat age-related organ dysfunction and decline.