In conclusion, we not only reveal that E2/ER subtypes mediate anti-inflammation and vasorelaxation via genomic and nongenomic actions in septic mice, but also elucidate that endothelial ER subtypes reduce proinflammatory cytokines and induce EDH-mediated vasorelaxation via PLC/IP3R/Ca2+ pathway, finally ameliorating sepsis-induced organ injury and survival rate. Here, ITPR1 is linked to Sepsis.