TY - JOUR
T1 - Sphingosine-1-Phosphate Attenuates Lipopolysaccharide-Induced Pericyte Loss via Activation of Rho-A and MRTF-A
AU - Abdel Rahman, Farah
AU - D'Almeida, Sascha
AU - Zhang, Tina
AU - Asadi, Morad
AU - Bozoglu, Tarik
AU - Bongiovanni, Dario
AU - Von Scheidt, Moritz
AU - Dietzel, Steffen
AU - Schwedhelm, Edzard
AU - Hinkel, Rabea
AU - Laugwitz, Karl Ludwig
AU - Kupatt, Christian
AU - Ziegler, Tilman
N1 - Publisher Copyright:
© 2020. Thieme. All rights reserved.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - 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.
AB - 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.
KW - adhesion molecules
KW - inflammation
KW - vascular disintegration
UR - http://www.scopus.com/inward/record.url?scp=85092618045&partnerID=8YFLogxK
U2 - 10.1055/s-0040-1716844
DO - 10.1055/s-0040-1716844
M3 - Article
C2 - 33011963
AN - SCOPUS:85092618045
SN - 0340-6245
VL - 121
SP - 341
EP - 350
JO - Thrombosis and Haemostasis
JF - Thrombosis and Haemostasis
IS - 3
ER -