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.
Highlights
Tie-2 is an endothelial-specific receptor tyrosine kinase that is predominantly expressed in the vascular endothelium
We further revealed that disruption of angiopoietins/Tie-2 and HIF-2α /Notch[3] signaling pathways may be responsible for LPS-induced impairment of pericyte/EC coverage and microvascular dysfunction
Deletion of prolyl hydroxylase-2 (PHD2) significantly increased Notch[3] expression in mouse lung endothelial cell (MLEC) exposed to LPS (Fig. 7D)
Summary
Tie-2 is an endothelial-specific receptor tyrosine kinase that is predominantly expressed in the vascular endothelium. PHD2-HIF-2α axis has been reported to regulate the shape and stability of microvasculature[30,31,32] Based upon these findings, we hypothesize that LPS causes acute pericyte loss and microvascular dysfunction by the mechanism(s) involving disruption of Sirt3/angiopoietins/Tie-2 and HIF-2α /Notch[3] signaling pathways. Using loss- and gain- of function approaches and endotoxin (LPS)-induced septic model, we have investigated the fundamental role of Sirt[3] in the regulation of endothelial/pericyte interactions, vascular integrity and permeability during sepsis. We further revealed that disruption of angiopoietins/Tie-2 and HIF-2α /Notch[3] signaling pathways may be responsible for LPS-induced impairment of pericyte/EC coverage and microvascular dysfunction
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