Intrinsic function of leptin receptor-regulated endothelial PD-L1

Programmed cell death ligand-1 (PD-L1) is an immune checkpoint protein expressed in vascular endothelial cells (ECs). In contrast to cancer, our understanding of endothelial PD-L1 in relation to metabolic syndromes and its vascular complications is less studied. For example, its regulation and intrinsic function remain unclear. Here, we showed that endothelial PD-L1 is regulated by leptin receptor signaling in male mice. In particular, endothelial PD-L1 expression is affected by leptin resistance. A lack of leptin receptors leads to PD-L1 downregulation in vascular ECs via posttranslational degradation. To understand the fundamental roles of endothelial PD-L1, RNA interference and selective knockout are employed in human endothelium and animals, respectively. Silencing or deleting endothelial PD-L1 expression delays cell cycle progression and proliferation due to rat sarcoma (RAS)/mitogen-activated protein kinase (MAPK) inactivation. In obesity, endothelial PD-L1 deficiency impairs the EC turnover and worsens the vascular function. Overall, we provide an insight into how endothelial PD-L1 contributes to vascular homeostasis, suggesting its pathophysiological importance in maintaining cellular turnover.