title: Sepsis-induced elevation in plasma serotonin facilitates endothelial hyperpermeability.
abstract: Hyperpermeability of the endothelial barrier and resulting microvascular leakage are a hallmark of sepsis. Our studies describe the mechanism by which serotonin (5-HT) regulates the microvascular permeability during sepsis. The plasma 5-HT levels are significantly elevated in mice made septic by cecal ligation and puncture (CLP). 5-HT-induced permeability of endothelial cells was associated with the phosphorylation of p21 activating kinase (PAK1), PAK1-dependent phosphorylation of vimentin (P-vimentin) filaments, and a strong association between P-vimentin and ve-cadherin. These findings were in good agreement with the findings with the endothelial cells incubated in serum from CLP mice. In vivo, reducing the 5-HT uptake rates with the 5-HT transporter (SERT) inhibitor, paroxetine blocked renal microvascular leakage and the decline in microvascular perfusion. Importantly, mice that lack SERT showed significantly less microvascular dysfunction after CLP. Based on these data, we propose that the increased endothelial 5-HT uptake together with 5-HT signaling disrupts the endothelial barrier function in sepsis. Therefore, regulating intracellular 5-HT levels in endothelial cells represents a novel approach in improving sepsis-associated microvascular dysfunction and leakage. These new findings advance our understanding of the mechanisms underlying cellular responses to intracellular/extracellular 5-HT ratio in sepsis and refine current views of these signaling processes during sepsis.
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, US.
authors.forename: Yicong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, US.
authors.forename: Coedy
authors.initials: C
authors.lastname: Hadden
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, US.
authors.forename: Anthonya
authors.initials: A
authors.lastname: Cooper
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, US.
authors.forename: Asli
authors.initials: A
authors.lastname: Ahmed
authors.affiliation: Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, US.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Departments of Physiology University of Arkansas for Medical Sciences, Little Rock, Arkansas, US.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Lupashin
authors.affiliation: Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, US.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Mayeux
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, US.
authors.forename: Fusun
authors.initials: F
authors.lastname: Kilic
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D010949:Plasma / Q000737:chemistry*; D018805:Sepsis / Q000473:pathology* / Q000503:physiopathology*; D012701:Serotonin / Q000097:blood* / Q000378:metabolism*; D017366:Serotonin Receptor Agonists
chemical_list: D017366:Serotonin Receptor Agonists; D012701:Serotonin