New mechanisms and therapeutic approaches to regulate vascular permeability in systemic inflammation

This review summarizes mechanisms that regulate endothelial vascular permeability in health and disease. In systemic inflammation, the endothelial barrier integrity is disrupted, which exacerbates vascular permeability, leading to organ failure and death. Herein we provide an overview of emerging therapeutic targets to reverse barrier dysfunction and preserve vascular permeability in inflammatory diseases like sepsis.

Endothelial barrier function is regulated in part by the endothelial cell-specific protein, Roundabout 4 (ROBO4), and vascular endothelial (VE)-cadherin, a critical adherens junction protein, which act in concert to suppresses vascular permeability by stabilizing endothelial cell-cell interactions. We recently discovered a pathway by which activation of coagulation factor XI (FXI) enhances the cleavage of VE-cadherin by the metalloproteinase ADAM10, contributing to sepsis-related endothelial damage and loss of barrier function. Targeting FXI improved survival and reduced sVE-cadherin levels in a baboon model of sepsis while enhancing Robo4 expression decreased mortality in LPS-treated mice.

Endothelial cell barrier dysfunction is a hallmark of excessive immune responses characteristic of systemic inflammatory diseases such as sepsis. Advances in understanding the molecular mechanisms regulating vascular permeability, for instance the newly discovered roles of FXI or ROBO4, may help identify novel therapeutic targets for mitigating vascular hyperpermeability in septic patients.