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.

Sirtuin 3 deficiency does not alter host defenses against bacterial and fungal infections

“…To address that question, SIRT3 −/− mice with additional backcrosses should be tested. SIRT3 +/+ mice had a minor yet significant survival advantage (10% vs 0% survival in SIRT3 +/+ vs SIRT3 −/− mice) in a highly stringent model of endotoxemia 38 , suggesting that SIRT3 may provide benefits in sterile, deep inflammatory, processes. Unfortunately, the cytokine response was not reported.…”

Ablation of SIRT3 causes coronary microvascular dysfunction and impairs cardiac recovery post myocardial ischemia

“…Ang-1 is critical for the vascular integrity, stability, and EC survival, as well as pericyte recruitment. Our recent study demonstrated a critical role of SIRT3 in LPS-mediated pericyte loss, vascular leakage and cardiac dysfunction [39]. Microvascular dysfunction could be related to the changes in both function and morphology of the microcirculation [5;40].…”

Concise Review: Fat and Furious: Harnessing the Full Potential of Adipose-Derived Stromal Vascular Fraction

“…Loss of pericytes is an early hallmark of diabetic retinopathy and leads to microaneurysm due to reduced vessel integrity . Inducing inflammation with lipopolysaccharide treatment leads to pericyte loss and microvascular dysfunction in a mouse model of sepsis . Furthermore, loss of pericytes accelerates Aβ accumulation, the appearance of Tau pathology and neuronal degeneration in mice overexpressing Aβ‐precursor protein .…”