title: LPS causes pericyte loss and microvascular dysfunction via disruption of Sirt3/angiopoietins/Tie-2 and HIF-2α/Notch3 pathways.
abstract: Recent studies reveal a crucial role of pericyte loss in sepsis-associated microvascular dysfunction. Sirtuin 3 (SIRT3) mediates histone protein post-translational modification related to aging and ischemic disease. This study investigated the involvement of SIRT3 in LPS-induced pericyte loss and microvascular dysfunction. Mice were exposed to LPS, expression of Sirt3, HIF-2α, Notch3 and angiopoietins/Tie-2, pericyte/endothelial (EC) coverage and vascular permeability were assessed. Mice treated with LPS significantly reduced the expression of SIRT3, HIF-2α and Notch3 in the lung. Furthermore, exposure to LPS increased Ang-2 while inhibited Ang-1/Tie-2 expression with a reduced pericyte/EC coverage. Intriguingly, knockout of Sirt3 upregulated Ang-2, but downregulated Tie-2 and HIF-2α/Notch3 expression which resulted in a dramatic reduction of pericyte/EC coverage and exacerbation of LPS-induced vascular leakage. Conversely, overexpression of Sirt3 reduced Ang-2 expression and increased Ang-1/Tie-2 and HIF-2α/Notch3 expression in the LPS treated mice. Overexpression of Sirt3 further prevented LPS-induced pericyte loss and vascular leakage. This was accompanied by a significant reduction of the mortality rate. Specific knockout of prolyl hydroxylase-2 (PHD2) increased HIF-2α/Notch3 expression, improved pericyte/EC coverage and reduced the mortality rate in the LPS-treated mice. Our study demonstrates the importance of SIRT3 in preserving vascular integrity by targeting pericytes in the setting of LPS-induced sepsis.
authors: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, 39216, USA.
authors: Heng
authors: H
authors: Zeng
authors: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, 39216, USA.
authors: Xiaochen
authors: X
authors: He
authors: School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
authors: Qin-Hui
authors: QH
authors: Tuo
authors: School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
authors: Duan-Fang
authors: DF
authors: Liao
authors: Emergency Department of China-Japan Friendship Hospital, Beijing, 100029, China.
authors: Guo-Qiang
authors: GQ
authors: Zhang
authors: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, 39216, USA.
authors: Jian-Xiong
authors: JX
authors: Chen
mesh_terms: D042682:Angiopoietins / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D042783:Endothelial Cells; D006321:Heart / Q000503:physiopathology; D007249:Inflammation / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung; D018345:Mice, Knockout; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D008954:Models, Biological; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000071656:Receptor, Notch3 / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D056566:Sirtuin 3 / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D042682:Angiopoietins; D051792:Basic Helix-Loop-Helix Proteins; D008070:Lipopolysaccharides; D000071656:Receptor, Notch3; D042787:Receptor, TIE-2; D056566:Sirtuin 3; D000099162:Endothelial PAS Domain-Containing Protein 1; C499373:Notch3 protein, mouse; C079086:Tek protein, mouse