Protective mechanism of the selective vasopressin V1A receptor agonist selepressin against endothelial barrier dysfunction

Nektarios Barabutis, Margarita Marinova, Pavel Solopov, Mohammad A Uddin, Glenn E Croston, Torsten M Reinheimer, John D Catravas
Journal of Pharmacology and Experimental Therapeutics 2020 September 17
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 V1A receptor (V1AR) agonists have shown promise in the treatment of sepsis, increasing blood pressure and reducing vascular hyperpermeability. The effects of the selective V1AR-selective agonist, selepressin, have been investigated in an in vitro model of thrombin-, VEGF-, angiopoietin 2-, and 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 V1AR, as well as by atosiban, an antagonist of the human V1AR. P53 appears to be involved in mediating these palliative effects, since selepressin strongly induced its expression levels, suppressed the inflammatory RhoA/MLC2 pathway and triggered the barrier protective effects of the GTPase Rac1. We conclude that V1AR-selective agonists, such as selepressin, may prove useful in the improvement of endothelial barrier function in the management of severe sepsis. Significance Statement A cardinal sign of sepsis, a serious disease with significant mortality and no specific treatment, is pulmonary endothelial barrier dysfunction that leads to pulmonary edema. Here we present evidence that in cultured human lug microvascular endothelial cells, the synthetic, selective V1AR agonist, selepressin, protects against endothelial barrier dysfunction caused by four different edemogenic agents, suggesting a potential role of selepressin in the clinical management of sepsis.

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