Revisiting endothelial PD-L1 as an endogenous gatekeeper to vascular homeostasis

Dysfunctional endothelial cells (ECs) are the main cause underpinning the vascular complications in metabolic syndromes like obesity. Programmed cell death ligand-1 (PD-L1; also known as CD274 or B7-H1) is a checkpoint protein expressed ubiquitously, including vascular ECs. It is known to suppress immunogenic responses upon the engagement with programmed cell death-1 (PD-1) on T-lymphocytes primarily. Beyond immunity, the PD-L1 pathway was recently identified to regulate multiple biological processes intrinsically. However, regardless of physiological or metaflammatory states, the immune-independent role of PD-L1 signaling remains poorly understood in EC biology. In the current study, we aimed to investigate the pathological implication and functional importance of endothelial PD-L1 during obesity. Based on multiple models, we showed leptin signaling is required for the endothelial PD-L1 expression. However, in obese mice, the exogenous leptin injection failed to stimulate the PD-L1 level in the aortic endothelium, suggesting that leptin resistance may hinder the PD-L1 expression. To further characterize the importance of PD-L1 to EC function, silencing the PD-L1 expression in human ECs impaired the cellular turnover as observed by cycle arrest and decreased proliferation. We also employed the Cre/loxP technique to generate the first-reported EC-specific PD-L1 knockout (Pdl1 ECKO ) mice and their wildtype counterpart (Pdl1 ECWT ). Upon diet-induced obesity, loss of endothelial PD-L1 elicited stronger inflammatory responses and oxidative stress which hampered the vasoreactivity of mouse aortas. In addition, our findings unmasked endothelial PD-L1 delays the onset of pathological vascular remodeling, highlighting its protective role against stress challenges. Altogether, our study advances our understanding of PD-L1 function in vascular biology, particularly its role in intrinsic regulation. This study is supported by the General Research Fund 14105022 from Hong Kong Research Grant Council. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.