Thromb Haemost 2021; 121(03): 341-350
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
› Institutsangaben
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



Publikationsverlauf

Eingereicht: 08. April 2020

Angenommen: 13. August 2020

Artikel online veröffentlicht:
04. Oktober 2020

© 2020. Thieme. All rights reserved.

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  • References

  • 1 Lee WL, Slutsky AS. Sepsis and endothelial permeability. N Engl J Med 2010; 363 (07) 689-691
  • 2 Herwig MC, Tsokos M, Hermanns MI, Kirkpatrick CJ, Müller AM. Vascular endothelial cadherin expression in lung specimens of patients with sepsis-induced acute respiratory distress syndrome and endothelial cell cultures. Pathobiology 2013; 80 (05) 245-251
  • 3 Boisramé-Helms J, Kremer H, Schini-Kerth V, Meziani F. Endothelial dysfunction in sepsis. Curr Vasc Pharmacol 2013; 11 (02) 150-160
  • 4 Bongiovanni D, Ziegler T, D'Almeida S. et al. Thymosin β4 attenuates microcirculatory and hemodynamic destabilization in sepsis. Expert Opin Biol Ther 2015; 15 (Suppl. 01) S203-S210
  • 5 Ziegler T, Horstkotte J, Schwab C. et al. Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis. J Clin Invest 2013; 123 (Suppl. 08) 3436-3445
  • 6 Spiegel S, Milstien S. Functions of the multifaceted family of sphingosine kinases and some close relatives. J Biol Chem 2007; 282 (04) 2125-2129
  • 7 Kono M, Mi Y, Liu Y. et al. The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis. J Biol Chem 2004; 279 (28) 29367-29373
  • 8 Jung B, Obinata H, Galvani S. et al. Flow-regulated endothelial S1P receptor-1 signaling sustains vascular development. Dev Cell 2012; 23 (03) 600-610
  • 9 Lee MJ, Thangada S, Claffey KP. et al. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell 1999; 99 (03) 301-312
  • 10 Paik JH, Skoura A, Chae SS. et al. Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. Genes Dev 2004; 18 (19) 2392-2403
  • 11 Winkler MS, Nierhaus A, Holzmann M. et al. Decreased serum concentrations of sphingosine-1-phosphate in sepsis. Crit Care 2015; 19: 372
  • 12 Bish LT, Morine K, Sleeper MM. et al. Adeno-associated virus (AAV) serotype 9 provides global cardiac gene transfer superior to AAV1, AAV6, AAV7, and AAV8 in the mouse and rat. Hum Gene Ther 2008; 19 (12) 1359-1368
  • 13 Rehberg M, Krombach F, Pohl U, Dietzel S. Label-free 3D visualization of cellular and tissue structures in intact muscle with second and third harmonic generation microscopy. PLoS One 2011; 6 (11) e28237
  • 14 Gavard J, Gutkind JS. VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 2006; 8 (11) 1223-1234
  • 15 Venkiteswaran K, Xiao K, Summers S. et al. Regulation of endothelial barrier function and growth by VE-cadherin, plakoglobin, and beta-catenin. Am J Physiol Cell Physiol 2002; 283 (03) C811-C821
  • 16 Yamada S, Pokutta S, Drees F, Weis WI, Nelson WJ. Deconstructing the cadherin-catenin-actin complex. Cell 2005; 123 (05) 889-901
  • 17 Dorn T, Kornherr J, Parrotta EI. et al. Interplay of cell-cell contacts and RhoA/MRTF-A signaling regulates cardiomyocyte identity. EMBO J 2018; 37 (12) e98133
  • 18 Zhang XE, Adderley SP, Breslin JW. Activation of RhoA, but not Rac1, mediates early stages of S1P-induced endothelial barrier enhancement. PLoS One 2016; 11 (05) e0155490
  • 19 Hinkel R, Trenkwalder T, Petersen B. et al. MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2. Nat Commun 2014; 5: 3970
  • 20 Hall-Glenn F, De Young RA, Huang BL. et al. CCN2/connective tissue growth factor is essential for pericyte adhesion and endothelial basement membrane formation during angiogenesis. PLoS One 2012; 7 (02) e30562
  • 21 Hanna M, Liu H, Amir J. et al. Mechanical regulation of the proangiogenic factor CCN1/CYR61 gene requires the combined activities of MRTF-A and CREB-binding protein histone acetyltransferase. J Biol Chem 2009; 284 (34) 23125-23136
  • 22 Austin KM, Nguyen N, Javid G, Covic L, Kuliopulos A. Noncanonical matrix metalloprotease-1-protease-activated receptor-1 signaling triggers vascular smooth muscle cell dedifferentiation and arterial stenosis. J Biol Chem 2013; 288 (32) 23105-23115
  • 23 Pfister F, Feng Y, vom Hagen F. et al. Pericyte migration: a novel mechanism of pericyte loss in experimental diabetic retinopathy. Diabetes 2008; 57 (09) 2495-2502
  • 24 Zehendner CM, Wedler HE, Luhmann HJ. A novel in vitro model to study pericytes in the neurovascular unit of the developing cortex. PLoS One 2013; 8 (11) e81637
  • 25 Zeng H, He X, Tuo QH, Liao DF, Zhang GQ, Chen JX. LPS causes pericyte loss and microvascular dysfunction via disruption of Sirt3/angiopoietins/Tie-2 and HIF-2α/Notch3 pathways. Sci Rep 2016; 6: 20931
  • 26 Wallez Y, Cand F, Cruzalegui F. et al. Src kinase phosphorylates vascular endothelial-cadherin in response to vascular endothelial growth factor: identification of tyrosine 685 as the unique target site. Oncogene 2007; 26 (07) 1067-1077
  • 27 Orsenigo F, Giampietro C, Ferrari A. et al. Phosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular permeability in vivo. Nat Commun 2012; 3: 1208
  • 28 Gavard J, Patel V, Gutkind JS. Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev Cell 2008; 14 (01) 25-36
  • 29 Dejana E, Orsenigo F, Lampugnani MG. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 2008; 121 (Pt 13): 2115-2122
  • 30 Hughes DP, Marron MB, Brindle NP. The antiinflammatory endothelial tyrosine kinase Tie2 interacts with a novel nuclear factor-kappaB inhibitor ABIN-2. Circ Res 2003; 92 (06) 630-636
  • 31 Kobayashi H, DeBusk LM, Babichev YO, Dumont DJ, Lin PC. Hepatocyte growth factor mediates angiopoietin-induced smooth muscle cell recruitment. Blood 2006; 108 (04) 1260-1266
  • 32 Kontos CD, Stauffer TP, Yang WP. et al. Tyrosine 1101 of Tie2 is the major site of association of p85 and is required for activation of phosphatidylinositol 3-kinase and Akt. Mol Cell Biol 1998; 18 (07) 4131-4140
  • 33 Reinhard NR, Mastop M, Yin T. et al. The balance between Gαi-Cdc42/Rac and Gα12/13-RhoA pathways determines endothelial barrier regulation by sphingosine-1-phosphate. Mol Biol Cell 2017; 28 (23) 3371-3382
  • 34 Duan X, Liu J, Dai XX. et al. Rho-GTPase effector ROCK phosphorylates cofilin in actin-meditated cytokinesis during mouse oocyte meiosis. Biol Reprod 2014; 90 (02) 37
  • 35 Maekawa M, Ishizaki T, Boku S. et al. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 1999; 285 (5429): 895-898