Abstract 649: Endothelial-derived Sphingolipids Preserve Systemic Vascular Function And Blood Pressure

Endothelial dysfunction is a critical event in many cardiovascular diseases including hypertension. Although lipid signaling is implicated in endothelial dysfunction and cardiovascular diseases, specific molecular mechanisms are poorly understood. Here we report a novel regulation of endothelial sphingolipid synthesis by Nogo-B, membrane protein of the endoplasmic reticulum that modulates local sphingolipid production with direct effects on vascular function and blood pressure. Nogo-B inhibits serine palmitoyltransferase, rate-limiting enzyme of the sphingolipid de novo synthesis, controlling endothelial sphingosine 1-phosphate production and its autocrine G-protein-coupled receptor-dependent signaling actions. Mice lacking Nogo-B are hypotensive (90.1±1.6 vs. 119.9±2.6 mmHg WT mice), resistant to Ang-II (500ng/Kg/min)-induced hypertension (150.4±2.5 vs. 108.4±1.5 mmHg, compared to WT mice, 24 days after AngII infusion), and preserve endothelial function and nitric oxide release. Pharmacological inhibition of serine palmitoyltransferase with myriocin in mice that lack Nogo-B reinstated endothelial dysfunction and Ang-II-induced hypertension (143.9±1.5 vs. 90.1±1.6 mmHg, myriocin vs. vehicle treated Nogo-A/B-/- mice). Our study identifies Nogo-B as a key inhibitor of local sphingolipid synthesis and indicates that autocrine sphingolipids signaling within the endothelium are critical for vascular function and blood pressure homeostasis.