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

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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.