Supplemental Digital Content is available in the text. 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.

中文翻译：

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内皮鞘脂从头合成通过神经酰胺调节信号转导和 NO 来控制血压

补充数字内容在文本中可用。神经酰胺是通过两种主要机制调节各种细胞过程的鞘脂：作为第二信使和调节膜生物物理特性，特别是脂筏，重要的信号平台。鞘脂水平的改变与许多心血管疾病有关，包括高血压、动脉粥样硬化和糖尿病相关疾病；然而，神经酰胺影响内皮功能的分子机制仍然知之甚少。在这方面，我们通过删除 Sptlc2（丝氨酸棕榈酰转移酶的长链亚基 2）——该途径的第一种酶，产生了内皮鞘脂从头生物合成缺陷的小鼠。我们的研究表明，内皮鞘脂的从头产生对于调节 (1) 响应 NO 激动剂的信号转导以及主要通过神经酰胺、(2) 静息 eNOS（内皮 NO 合酶）磷酸化和（3）血压稳态是必要的。具体而言，我们的研究结果表明，C16:0-Cer 在保持由酪氨酸激酶和 GPCR（G 蛋白偶联受体）诱导的血管舒张中发挥主要作用，Gq 偶联受体除外，而 C24:0-和 C24:1-Cer 控制血流诱导的血管舒张。在体外和体内补充 C16:0-Cer 可恢复内皮细胞信号传导和血管张力调节。这项研究揭示了本地产生的神经酰胺，特别是 C16:0-、C24:0- 和 C24:1-Cer 在血管和血压稳态中的重要作用，并建立内皮细胞作为血浆神经酰胺的主要来源。临床上，特定血浆神经酰胺比率是主要心血管事件的独立预测因子。我们的数据还表明，血浆神经酰胺可能表明内皮的患病状态。