Untie-ing the role of the Angiopoientin/Tie2 system in the microvascular response to endotoxemia

PhD ceremony: Ms. N.F. Kurniati, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Untie-ing the role of the Angiopoientin/Tie2 system in the microvascular response to endotoxemia

Promotor(s): prof. G. Molema, prof. P. Heeringa, prof. M.M.R.F. Struys

Faculty: Medical Sciences

A number of pro-inflammatory stimuli can activate endothelial cells, resulting in an increase of expression of endothelial adhesion molecules and loss of vascular integrity. The Angiopoietin (Ang)/Tie2 system is one of the systems involved in the sensitization of the endothelial cell for pro-inflammatory activation and in the control of vascular integrity. The role of the Ang/Tie2 system during endotoxemia, in particular in response to lipopolysaccharide (LPS) induced organ inflammation was studied.

LPS affected the expression of the Ang/Tie2 system. The expression of Tie2 and Ang2 was downregulated respectively upregulated, at least in 3 organs studied, i.e., lungs, liver, and kidneys. The renal expression changes of this system did, however, not play a major role in LPS-induced renal albuminuria. An increase in Ang2 expression, but not loss of Tie2 expression, was associated with induction of glomeruli-restricted E-selectin expression in response to LPS. Furthermore, the mechanism of LPS-induced loss of Tie2 expression in vivo and in vitro was studied. We found that the loss of Tie2 was not due to a direct effect of LPS or TNF-α, one of cytokines released upon LPS administration, nor was it due to an interaction of endothelial cells with neutrophils. From our in vitro studies we concluded that the expression of Tie2 was mainly affected by flow, suggesting that LPS-induced lowering of blood flow is the likely cause of loss of Tie2 expression in vivo.