See also Raife TJ, Lentz SR. The benefits of excess EPCR. This issue, pp 1349-50.Summary. Previous studies have shown that blocking endothelial protein C receptor (EPCR)-protein C interaction results in about an 88% decrease in circulating activated protein C (APC) levels generated in response to thrombin infusion and exacerbates the response to Escherichia coli. To determine whether higher levels of EPCR expression on endothelial cells might further enhance the activation of protein C and protect the host during septicemia, we generated a transgenic mouse (Tie2-EPCR) line which placed the expression of EPCR under the control of the Tie2 promoter. The mice express abundant EPCR on endothelial cells not only on large vessels, but also on capillaries where EPCR is generally low. Tie2-EPCR mice show higher levels of circulating APC after thrombin infusion. Upon infusion with factor Xa and phospholipids, Tie2-EPCR mice generate more APC, less thrombin and are protected from fibrin/ogen deposition compared with wild type controls. The Tie2-EPCR animals also generate more APC upon lipopolysaccharide (LPS) challenge and have a survival advantage. These results reveal that overexpression of EPCR can protect animals against thrombotic or septic challenge.

Summary Background: Activated protein C (APC) protects the host from severe sepsis. Endothelial protein C receptor (EPCR) is expressed on both hematopoietic leukocytes and non‐hematopoietic endothelium, and plays a key role in protein C activation.Objectives: We explore the influence of EPCR deletion on the responses to lipopolysaccharide (LPS) and then determine whether the observed differences are due to loss of hematopoietic or non‐hematopoietic EPCR.Methods and results: After LPS challenge, EPCR null (Procr−/−) mice exhibited more thrombin and cytokine generation, neutrophil sequestration in the lung and a higher mortality rate than Procr+/− mice. Procr+/− BM/Procr−/− (non‐hematopoietic Procr−/−) and Procr−/− BM/Procr+/− (hematopoietic Procr−/−) chimeric mice were generated by bone marrow (BM) transplantation. Compared with control Procr+/− mice, non‐hematopoietic Procr−/− mice exhibited reduced protein C activation by thrombin and exaggerated responses to LPS challenge, whereas Procr+/− mice and hematopoietic Procr−/− mice exhibited similar protein C activation by thrombin and similar responses to LPS challenge.Conclusions: EPCR deletion exaggerates the host responses to LPS primarily due to deficiency of EPCR on the non‐hematopoietic cells.