Angiopoietin-like 4 to prevent endothelial damage during septic shock

Abstract

Regulation of endothelial barrier function is critical for vascular homeostasis but a comprehensive understanding of sepsis-induced endothelial injury involved in organ failure is lacking. We have previously demonstrated that recombinant human Angiopoietin-like-4 (ANGPTL4) protects vascular integrity in the heart, reduces cardiac edema and no-reflow acutely after acute myocardial infarction (AMI). We have also shown that ANGPTL4 has protective effects on the cerebrovascular and functional damage after ischaemic stroke that shares some pathophysiological factors with AMI. Given the strong association between vascular barrier integrity and endothelial injury markers for predicting higher mortality in shocks, we here sought to evaluate the cardiovascular impact of a novel pharmacological strategy that preserves microvascular integrity aimed at reducing endothelial damage and fluid extravasation, in order to improve perfusion and reduce organ failure and death. Septic shock was induced in adult mice using lipopolysaccharides (LPS). Vascular leakage (total weight/dry weight) was assessed in highly metabolic tissues such as liver, kidneys, lungs and heart by gravimetry in control mice vs mice injected with recombinant human Angiopoietin-like-4 (ANGPTL4). To go further, integrity of tight junctions was studied by using endothelial cells treated with LPS and treated or not with ANGPTL4. Following septic shock, our results demonstrate that injection of recombinant human Angiopoietin-like-4 (ANGPTL4) was able to protect vascular barrier integrity by decreasing fluid extravasation in cardiorespiratory system. In addition, we demonstrate that ANGPTL4 was able to preserve the integrity of endothelial cells junctions after LPS treatment. These results show that ANGPTL4 is a regulator of endothelial barrier integrity during septic shock. This discovery of the vascular protective effects of ANGPTL4, thus being crucial for preventing endothelial damage during septic shock, is one of the first examples of the validity of applying vascular permeability-limiting drugs in shock states. Its therapeutic potential in other types of shocks is also presently under investigation.