Signal Transduction and Gene Regulation in the Endothelium

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.

Automated summary

S1P and its receptors (S1PRs) play important roles in vascular development, homeostasis, and diseases as well-studied examples of GPCR signaling axis. The rapid biochemical cascades involved in S1P signaling are well understood, but the gene-expression regulation by S1PRs is less clear. This review focuses on how S1PRs regulate nuclear chromatin changes and gene transcription to modulate vascular and lymphatic endothelial phenotypic changes during embryonic development and adult homeostasis. These findings are crucial for understanding stimulus-evoked gene regulation in the vascular endothelium and developing therapeutic drugs for autoimmune and vascular diseases, considering the adverse events caused by S1PR-targeted drugs.