Abstract

Sepsis and septic shock are among the most common causes of death in the intensive care unit; advanced therapeutic approaches are thus urgently needed. Vascular hyperpermeability represents a major manifestation of severe sepsis and is responsible for the ensuing organ dysfunction and failure. Vasopressin V_1A receptor (V_1AR) agonists have shown promise in the treatment of sepsis, increasing blood pressure, and reducing vascular hyperpermeability. The effects of the selective V_1AR-selective agonist selepressin have been investigated in an in vitro model of thrombin-, vascular endothelial growth factor–, angiopoietin 2–, and lipopolysaccharide (LPS)-induced pulmonary microvascular endothelial hyperpermeability. Results suggest that selepressin counteracts the effects of all four endothelial barrier disruptors in a concentration-dependent manner, as reflected in real-time measurements of vascular permeability by means of transendothelial electrical resistance. Further, selepressin protected the barrier integrity against the LPS-mediated corruption of the endothelial monolayer integrity, as captured by VE-cadherin and actin staining. The protective effects of selepressin were abolished by silencing of the vasopressin V_1AR, as well as by atosiban, an antagonist of the human V_1AR. p53 appears to be involved in mediating these palliative effects, since selepressin strongly induced its expression levels, suppressed the inflammatory RhoA/myosin light chain2 pathway, and triggered the barrier-protective effects of the GTPase Rac1. We conclude that V_1AR-selective agonists, such as selepressin, may prove useful in the improvement of endothelial barrier function in the management of severe sepsis.