Endothelial dysfunction is a critical factor in many cardiovascular diseases, including hypertension. Although lipid signaling has been implicated in endothelial dysfunction and cardiovascular disease, specific molecular mechanisms are poorly understood. Here we report that Nogo-B, a membrane protein of the endoplasmic reticulum, regulates endothelial sphingolipid biosynthesis with direct effects on vascular function and blood pressure. Nogo-B inhibits serine palmitoyltransferase, the rate-limiting enzyme of the de novo sphingolipid biosynthetic pathway, thereby controlling production of endothelial sphingosine 1-phosphate and autocrine, G protein–coupled receptor–dependent signaling by this metabolite. Mice lacking Nogo-B either systemically or specifically in endothelial cells are hypotensive, resistant to angiotensin II–induced hypertension and have preserved endothelial function and nitric oxide release. In mice that lack Nogo-B, pharmacological inhibition of serine palmitoyltransferase with myriocin reinstates endothelial dysfunction and angiotensin II–induced hypertension. Our study identifies Nogo-B as a key inhibitor of local sphingolipid synthesis and shows that autocrine sphingolipid signaling within the endothelium is critical for vascular function and blood pressure homeostasis.
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This work was supported by European Cooperation in Science and Technology (COST) Action BM1005 European Network on Gasotransmitters (ENOG) to M.B.; US National Institutes of Health (NIH) R37-HL67330 and R01HL89934 to T.H.; NIH R01HL126913-01, a Harold S. Geneen Charitable Trust Award for Coronary Heart Disease Research and American Heart Association grant 11SDG5710010 to A.D.L.
The authors declare no competing financial interests.
Supplementary Figures 1–4 (PDF 6988 kb)
Nogo-B effect on vasoconstriction. (XLSX 39 kb)
Sphingolipid levels in vascular SMC and SPT assay in EC. (XLSX 36 kb)
Effects of W146 and myriocin on vascular tone regulation. (XLSX 73 kb)
Nogo-B excision in EC-Nogo-A/B-deficient and SMC-Nogo-A/B-deficient mice. (XLSX 46 kb)
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Cantalupo, A., Zhang, Y., Kothiya, M. et al. Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure. Nat Med 21, 1028–1037 (2015). https://doi.org/10.1038/nm.3934
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