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Nat Med. 2015 Sep;21(9):1028-1037. doi: 10.1038/nm.3934. Epub 2015 Aug 24.

Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure.

Author information

1
Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
2
Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
3
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
4
Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, Connecticut, USA.
5
Department of Anatomy and Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, New York, USA.
#
Contributed equally

Abstract

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.

Comment in

PMID:
26301690
PMCID:
PMC4692717
DOI:
10.1038/nm.3934
[Indexed for MEDLINE]
Free PMC Article

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