Endothelial Sphingolipid De Novo Synthesis Controls Blood Pressure by Regulating Signal Transduction and NO via Ceramide

Abstract

Ceramides are sphingolipids that modulate a variety of cellular processes via 2 major mechanisms: functioning as second messengers and regulating membrane biophysical properties, particularly lipid rafts, important signaling platforms. Altered sphingolipid levels have been implicated in many cardiovascular diseases, including hypertension, atherosclerosis, and diabetes mellitus–related conditions; however, molecular mechanisms by which ceramides impact endothelial functions remain poorly understood. In this regard, we generated mice defective of endothelial sphingolipid de novo biosynthesis by deleting the Sptlc2 (long chain subunit 2 of serine palmitoyltransferase)—the first enzyme of the pathway. Our study demonstrated that endothelial sphingolipid de novo production is necessary to regulate (1) signal transduction in response to NO agonists and, mainly via ceramides, (2) resting eNOS (endothelial NO synthase) phosphorylation, and (3) blood pressure homeostasis. Specifically, our findings suggest a prevailing role of C16:0-Cer in preserving vasodilation induced by tyrosine kinase and GPCRs (G-protein coupled receptors), except for Gq-coupled receptors, while C24:0- and C24:1-Cer control flow-induced vasodilation. Replenishing C16:0-Cer in vitro and in vivo reinstates endothelial cell signaling and vascular tone regulation. This study reveals an important role of locally produced ceramides, particularly C16:0-, C24:0-, and C24:1-Cer in vascular and blood pressure homeostasis, and establishes the endothelium as a key source of plasma ceramides. Clinically, specific plasma ceramides ratios are independent predictors of major cardiovascular events. Our data also suggest that plasma ceramides might be indicative of the diseased state of the endothelium.

Differential Expression of Sphingolipid Metabolizing Enzymes in Spontaneously Hypertensive Rats: A Possible Substrate for Susceptibility to Brain and Kidney Damage

“…Recent studies have pointed out a potential involvement of de novo biosynthesis of sphingolipids in hypertension and vascular diseases [ 29 , 30 ].…”

“…Although both hypertensive strains shared some defects in the expression of other genes involved in de novo sphingolipid synthesis, the reduction of SPTLCs clearly suggest a key role of this metabolic route in the pathogenesis of the cerebrovascular disease. In this context, recent evidence indicates that the endothelial de novo synthesis of sphingolipids regulates blood pressure and endothelial homeostasis [ 30 ], highlighting the critical role of de novo synthetized sphingolipids in vascular diseases. The current data may indicate that the de novo synthesis of sphingolipids could be perturbed in the SHRSP.…”

Why and how increased plasma ceramides predict future cardiovascular events?

“…1). In a recent publication, ceramide production by vascular endothelial cells was linked to preserving endothelial functionality and control of blood pressure [18]. The findings in the above-cited work also suggest that a large proportion of the circulating ceramides are produced by endothelial cells.…”

Sphingolipids in the Heart: From Cradle to Grave

“…While these biomarkers and diagnostic indicators represent advances in identifying and diagnosing CVD, the distinction between long chain (i.e., C16-C18) and very long chain (i.e., C20-C24) ceramides, which are generated by distinct ceramide synthase isoforms (CerS1/5/6 vs. CerS2/4, respectively) hints at potential mechanistic involvement. However, though much circulating lipid in general arises from liver, a detailed study demonstrated that circulating ceramides but not SM are derived from the endothelium of blood vessels (145). Interestingly the endothelium is functionally impaired in CVDs and could thus contribute to the plasma sphingolipid profile reported in HF.…”