title: Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure.
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.
authors: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
authors: Anna
authors: A
authors: Cantalupo
authors: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
authors: Yi
authors: Y
authors: Zhang
authors: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
authors: Milankumar
authors: M
authors: Kothiya
authors: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
authors: Sylvain
authors: S
authors: Galvani
authors: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
authors: Hideru
authors: H
authors: Obinata
authors: Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
authors: Mariarosaria
authors: M
authors: Bucci
authors: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.|Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Frank J
authors: FJ
authors: Giordano
authors: Department of Anatomy and Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, New York, USA.
authors: Xian-Cheng
authors: XC
authors: Jiang
authors: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
authors: Timothy
authors: T
authors: Hla
authors: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
authors: Annarita
authors: A
authors: Di Lorenzo
mesh_terms: D000818:Animals; D001794:Blood Pressure; D019556:COS Cells; D002522:Chlorocebus aethiops; D004730:Endothelium, Vascular / Q000502:physiology*; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D008246:Lysophospholipids / Q000502:physiology; D008297:Male; D051379:Mice; D009185:Myelin Proteins / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D000070798:Nogo Proteins; D049349:Receptors, Lysosphingolipid / Q000502:physiology; D013107:Sphingolipids / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000502:physiology
chemical_list: D008246:Lysophospholipids; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603199:RTN4 protein, human; D049349:Receptors, Lysosphingolipid; C000603201:Rtn4 protein, mouse; D013107:Sphingolipids; C060506:sphingosine 1-phosphate; D052250:Nitric Oxide Synthase Type III; D013110:Sphingosine