Sphingosine-1-Phosphate Attenuates Lipopolysaccharide-Induced Pericyte Loss via Activation of Rho-A and MRTF-A

Farah Abdel Rahman, Sascha D'Almeida, Tina Zhang, Morad Asadi, Tarik Bozoglu, Dario Bongiovanni, Moritz Von Scheidt, Steffen Dietzel, Edzard Schwedhelm, Rabea Hinkel, Karl Ludwig Laugwitz, Christian Kupatt, Tilman Ziegler

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The high mortality seen in sepsis is caused by a systemic hypotension in part owing to a drastic increase in vascular permeability accompanied by a loss of pericytes. As has been shown previously, pericyte retention in the perivascular niche during sepsis can enhance the integrity of the vasculature and promote survival via recruitment of adhesion proteins such as VE-cadherin and N-cadherin. Sphingosine-1-phosphate (S1P) represents a lipid mediator regulating the deposition of the crucial adhesion molecule VE-cadherin at sites of interendothelial adherens junctions and of N-cadherin at endothelial-pericyte adherens junctions. Furthermore, in septic patients, S1P plasma levels are decreased and correlate with mortality in an indirectly proportional way. In the present study, we investigated the potential of S1P to ameliorate a lipopolysaccharide-induced septic hypercirculation in mice. Here we establish S1P as an antagonist of pericyte loss, vascular hyperpermeability, and systemic hypotension, resulting in an increased survival in mice. During sepsis S1P preserved VE-cadherin and N-cadherin deposition, mediated by a reduction of Src and cadherin phosphorylation. At least in part, this effect is mediated by a reduction of globular actin and a subsequent increase in nuclear translocation of MRTF-A (myocardin-related transcription factor A). These findings indicate that S1P may counteract pericyte loss and microvessel disassembly during sepsis and additionally emphasize the importance of pericyte-endothelial interactions to stabilize the vasculature.

Original languageEnglish
Pages (from-to)341-350
Number of pages10
JournalThrombosis and Haemostasis
Volume121
Issue number3
DOIs
StatePublished - 1 Mar 2021
Externally publishedYes

Keywords

  • adhesion molecules
  • inflammation
  • vascular disintegration

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