Levesque Michel V, Hla Timothy
Vascular Biology Program, Boston Children's Hospital and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cold Spring Harb Perspect Med. 2023 Jan 3;13(1):a041153. doi: 10.1101/cshperspect.a041153.
Extracellular signals act on G-protein-coupled receptors (GPCRs) to regulate homeostasis and adapt to stress. This involves rapid intracellular post-translational responses and long-lasting gene-expression changes that ultimately determine cellular phenotype and fate changes. The lipid mediator sphingosine 1-phosphate (S1P) and its receptors (S1PRs) are examples of well-studied GPCR signaling axis essential for vascular development, homeostasis, and diseases. The biochemical cascades involved in rapid S1P signaling are well understood. However, gene-expression regulation by S1PRs are less understood. In this review, we focus our attention to how S1PRs regulate nuclear chromatin changes and gene transcription to modulate vascular and lymphatic endothelial phenotypic changes during embryonic development and adult homeostasis. Because S1PR-targeted drugs approved for use in the treatment of autoimmune diseases cause substantial vascular-related adverse events, these findings are critical not only for general understanding of stimulus-evoked gene regulation in the vascular endothelium, but also for therapeutic development of drugs for autoimmune and perhaps vascular diseases.
细胞外信号作用于G蛋白偶联受体（GPCRs）以调节体内平衡并适应应激。这涉及快速的细胞内翻译后反应和持久的基因表达变化，最终决定细胞表型和命运改变。脂质介质1-磷酸鞘氨醇（S1P）及其受体（S1PRs）是研究充分的GPCR信号轴的例子，对血管发育、体内平衡和疾病至关重要。参与快速S1P信号传导的生化级联反应已得到充分了解。然而，S1PRs对基因表达的调控尚不太清楚。在这篇综述中，我们将注意力集中在S1PRs如何调节核染色质变化和基因转录，以在胚胎发育和成年体内平衡期间调节血管和淋巴管内皮细胞的表型变化。由于批准用于治疗自身免疫性疾病的S1PR靶向药物会引起大量与血管相关的不良事件，这些发现不仅对于全面了解血管内皮中刺激诱发的基因调控至关重要，而且对于自身免疫性疾病以及可能的血管疾病的药物治疗开发也至关重要。
