Thromb Haemost
DOI: 10.1055/s-0040-1716844
Blood Cells, Inflammation and Infection

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

Farah Abdel Rahman
1  Klinik & Poliklinik für Innere Medizin I, Klinikum Rechts der Isar, TU Munich, Munich, Germany
2  DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
,
Sascha d'Almeida
1  Klinik & Poliklinik für Innere Medizin I, Klinikum Rechts der Isar, TU Munich, Munich, Germany
,
Tina Zhang
1  Klinik & Poliklinik für Innere Medizin I, Klinikum Rechts der Isar, TU Munich, Munich, Germany
,
Morad Asadi
1  Klinik & Poliklinik für Innere Medizin I, Klinikum Rechts der Isar, TU Munich, Munich, Germany
,
Tarik Bozoglu
1  Klinik & Poliklinik für Innere Medizin I, Klinikum Rechts der Isar, TU Munich, Munich, Germany
,
Dario Bongiovanni
1  Klinik & Poliklinik für Innere Medizin I, Klinikum Rechts der Isar, TU Munich, Munich, Germany
2  DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
,
Moritz von Scheidt
2  DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
3  Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
,
Steffen Dietzel
4  Walter-Brendl-Center for Experimental Medicine, LMU Munich, Munich, Germany
,
Edzard Schwedhelm
5  Center for Experimental Medicine, Institute of Clinical Pharmacology and Toxicology, Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Rabea Hinkel
1  Klinik & Poliklinik für Innere Medizin I, Klinikum Rechts der Isar, TU Munich, Munich, Germany
2  DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
6  Institute for Cardiovascular Prevention, LMU Munich, Munich, Germany
,
Karl Ludwig Laugwitz
1  Klinik & Poliklinik für Innere Medizin I, Klinikum Rechts der Isar, TU Munich, Munich, Germany
2  DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
,
Christian Kupatt
1  Klinik & Poliklinik für Innere Medizin I, Klinikum Rechts der Isar, TU Munich, Munich, Germany
2  DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
,
1  Klinik & Poliklinik für Innere Medizin I, Klinikum Rechts der Isar, TU Munich, Munich, Germany
2  DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
› Author Affiliations
Funding This study was supported by the Deutsche Stiftung für Herzforschung (to T. Ziegler) and the Xeno SFB TRR 127 (to C. Kupatt).

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.

Supplementary Material



Publication History

Received: 08 April 2020

Accepted: 13 August 2020

Publication Date:
04 October 2020 (online)

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