Sphingosine‐1‐phosphate Enhances Mitochondrial Integrity and Endothelial Barrier Function Following Hemorrhagic Shock

Abstract

Excessive microvascular permeability is a serious complication involved in traumatic injury and inflammatory diseases. Sphingosine‐1‐phosphate (S1P) has known endothelial barrier‐protective properties, and has been shown to ameliorate microvascular leakage in a model of combined alcohol intoxication and hemorrhagic shock and resuscitation (HSR). However, the mechanisms of S1P‐induced barrier protection during HSR are unknown. In the current study, we tested the hypothesis that S1P could enhance endothelial barrier function during hemorrhagic shock by preserving the integrity of junction proteins and the endothelial glycocalyx, and protecting mitochondrial function. We used an established in vivo rat model of conscious HSR and assessed microvascular leakage, endothelial glycocalyx integrity, and mitochondrial function by intravital microscopy. Assessment of adherens junction protein localization was done by immunofluorescence confocal microscopy after HSR. Cultured rat intestinal microvascular endothelial cell (RIMEC) monolayers were used to test the ability of S1P to protect against glycocalyx shedding and endothelial barrier dysfunction caused by direct disruption of mitochondrial integrity due to inhibition of mitochondrial complex III. Our in vivo results show that S1P protects against HSR‐induced hyperpermeability, preserves the expression of adherens junctional proteins, and protects against glycocalyx degradation. S1P treatment during HSR also protects against mitochondrial membrane depolarization. Besides that, S1P protects RIMECs against mitochondrial dysfunction‐induced endothelial barrier dysfunction and glycocalyx degradation by blocking complex III inhibition. Our results show that S1P protects against HSR‐induced mitochondrial dysfunction in endothelial cells, which in turn improves the structure of the endothelial glycocalyx after HSR and allows for better junctional integrity, preventing excess microvascular permeability.Support or Funding InformationSupported by NIH grants R01HL098215, R01GM120774, R01HL070752 and R01GM097270.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.