The protective role of estrogen on endothelial and glycocalyx barriers after shock conditions: A microfluidic study

Abstract Background Sexual dimorphism has been demonstrated after major trauma and hemorrhage shock with protective effects related to female sex or estrogen. Traumatic endotheliopathy is an important component of trauma-induced coagulopathy. Components of endothelial barrier dysfunction include degradation of the endothelial glycocalyx and endothelial cellular injury. Estrogen modulates endothelial function via its membrane and cellular receptors. The effects of estrogen on the vascular endothelial barrier after trauma and hemorrhage shock are, however, unknown. This topic was studied in an in vitro model under flow conditions. Methods Monolayers of human umbilical vein endothelial cells were established in microfluidic flow devices. After overnight perfusion, cell monolayers were subjected to normoxic or hypoxic perfusion and then treated with either estrogen (as estradiol), testosterone (as dihydrotestosterone), or media alone. Endothelial activation/injury was indexed by soluble thrombomodulin and glycocalyx degradation by syndecan-1 and hyaluronic acid shedding as well as measurement of the thickness of the glycocalyx layer. The coagulation phenotype of the human umbilical vein endothelial cells was indexed by the relative values of the activities of tissue plasminogen activator and plasminogen activator inhibitor-1. Vascular endothelial growth factor was measured in cell culture supernatants using a solid-phase enzyme-linked immunosorbent assay. Results Treatment with estrogen but not testosterone mitigated the adverse effect of shock on endothelial and glycocalyx barrier properties. Our biomimetic model suggests a beneficial effect of estrogen administration after trauma and hemorrhage shock on the glycocalyx and endothelial barriers. Conclusion Early estrogen treatment after trauma and hemorrhage shock may be a useful adjunct to mitigating the development of traumatic endotheliopathy.