Rutgers Cancer Institute of New Jersey, Newark, NJ 07101.
Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103.
Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2220269120. doi: 10.1073/pnas.2220269120. Epub 2023 Aug 14.
The vascular endothelium from individual organs is functionally specialized, and it displays a unique set of accessible molecular targets. These serve as endothelial cell receptors to affinity ligands. To date, all identified vascular receptors have been proteins. Here, we show that an endothelial lung-homing peptide (CGSPGWVRC) interacts with C16-ceramide, a bioactive sphingolipid that mediates several biological functions. Upon binding to cell surfaces, CGSPGWVRC triggers ceramide-rich platform formation, activates acid sphingomyelinase and ceramide production, without the associated downstream apoptotic signaling. We also show that the lung selectivity of CGSPGWVRC homing peptide is dependent on ceramide production in vivo. Finally, we demonstrate two potential applications for this lipid vascular targeting system: i) as a bioinorganic hydrogel for pulmonary imaging and ii) as a ligand-directed lung immunization tool against COVID-19. Thus, C16-ceramide is a unique example of a lipid-based receptor system in the lung vascular endothelium targeted in vivo by circulating ligands such as CGSPGWVRC.
血管内皮细胞具有功能特异性，其表面存在一系列可及的分子靶点，这些靶点可作为内皮细胞的受体与配体结合。迄今为止，所有已鉴定的血管受体均为蛋白质。在这里，我们发现一种血管内皮肺靶向肽（CGSPGWVRC）与神经酰胺相互作用，神经酰胺是一种具有生物活性的鞘脂，可介导多种生物学功能。CGSPGWVRC 与细胞表面结合后会触发富含神经酰胺的平台形成，激活酸性神经鞘磷脂酶并产生神经酰胺，而不会引发相关的下游凋亡信号。我们还表明，CGSPGWVRC 归巢肽对肺的选择性依赖于体内神经酰胺的产生。最后，我们展示了该脂质血管靶向系统的两个潜在应用：i）作为用于肺部成像的生物无机水凝胶，ii）作为针对 COVID-19 的配体导向肺免疫工具。因此，C16-神经酰胺是一种独特的基于脂质的受体系统的例子，其在肺血管内皮细胞中的作用是由循环配体（如 CGSPGWVRC）靶向的。
