Endothelial Tie2 signaling plays a pivotal role in vascular barrier maintenance at baseline and after injury. We previously demonstrated that a sharp drop in Tie2 expression observed across various murine models of critical illnesses is associated with increased vascular permeability and mortality. Matrix metalloprotease (MMP)-14-mediated Tie2 ectodomain shedding has recently been recognized as a possible mechanism for Tie2 downregulation in sepsis. Here, we identified the exact MMP14-mediated Tie2 ectodomain cleavage sites and could show that pharmacological MMP14 blockade in experimental murine sepsis exerts barrier protective and anti-inflammatory effects predominantly through the attenuation of Tie2 cleavage to improve survival both in a pre-treatment and rescue approach. Overall, we show that protecting Tie2 shedding might offer a new therapeutic opportunity for the treatment of septic vascular leakage.
- Idowu, T. O.
- Etzrodt, V.
- Seeliger, B.
- Bolanos-Palmieri, P.
- Thamm, K.
- Haller, H.
- David, S.
Keywords
- *mmp14
- *Sepsis
- *Tie2
- *endothelial cells
- *immunology
- *inflammation
- *medicine
- *mouse
- *permeability
- *vascular barrier function