Paeoniflorin protects the vascular endothelial barrier in mice with sepsis by activating RXRα signaling.

Objective: Sepsis is a life-threatening condition characterized by organ dysfunction resulting from the body's aberrant response to infection. A primary indicator of early sepsis is vascular leakage due to endothelial injury. The immunomodulatory effects of paeoniflorin are well established. However, its effect on vascular endothelial injury in sepsis remains to be verified.

Methods: The sepsis model was established by cecal ligation and puncture (CLP), along with simultaneous administration of paeoniflorin. The therapeutic effectiveness of paeoniflorin was evaluated by assessing the survival rate, the bacterial load in blood and the histopathological lung tissue injury. The pulmonary vascular endothelial barrier integrity was assessed using immunofluorescence, western blot, Evans blue dye, and qPCR. Human umbilical vein endothelial cells (HUVECs) were used for in vitro validation and exploration of the underlying mechanisms.

Results: The CLP mice exhibited significant damage to pulmonary tissue and breakdown of endothelial barrier. Administration of paeoniflorin markedly improved survival rates, mitigated lung injury, and preserved the integrity of the pulmonary vascular endothelial barrier in CLP mice which was confirmed by in vitro experiments. Pharmacological mechanism studies showed that the protective effects of paeoniflorin on the vascular endothelium was achieved through activation of RXRα signaling, which could be reversed by RXRα knockdown.

Conclusion: Our experiments demonstrates the protective effect of paeoniflorin on the vascular endothelial barrier through activation of the RXRα, thereby offering potential therapeutic options for sepsis treatment. We also identified RXRα as a novel transcription factor for VE-cadherin, providing a potential new intervention target for vascular endothelial barrier damage in sepsis.