Reduced Tie2 in Microvascular Endothelial Cells Is Associated with Organ-Specific Adhesion Molecule Expression in Murine Health and Endotoxemia

Endothelial cells (ECs) in the microvasculature in organs are active participants in the

pathophysiology of sepsis. Tyrosine protein kinase receptor Tie2 (Tek; Tunica interna Endothelial

cell Kinase) is thought to play a role in their inflammatory response, yet data are inconclusive.

We investigated acute endotoxemia-induced changes in the expression of Tie2 and inflammationassociated

endothelial adhesion molecules E-selectin and VCAM-1 (vascular cell adhesion molecule-1)

in kidneys and lungs in inducible, EC-specific Tie2 knockout mice. The extent of Tie2 knockout in

healthy mice differed between microvascular beds, with low to absent expression in arterioles in

kidneys and in capillaries in lungs. In kidneys, Tie2 mRNA dropped more than 70% upon challenge

with lipopolysaccharide (LPS) in both genotypes, with no change in protein. In renal arterioles,

tamoxifen-induced Tie2 knockout was associated with higher VCAM-1 protein expression in healthy

conditions. This did not increase further upon challenge of mice with LPS, in contrast to the increased

expression occurring in control mice. Also, in lungs, Tie2 mRNA levels dropped within 4 h after LPS

challenge in both genotypes, while Tie2 protein levels did not change. In alveolar capillaries, where

tamoxifen-induced Tie2 knockout did not affect the basal expression of either adhesion molecule, a

4-fold higher E-selectin protein expression was observed after exposure to LPS compared to controls.

The here-revealed heterogeneous effects of absence of Tie2 in ECs in kidney and lung microvasculature

in health and in response to acute inflammatory activation calls for further in vivo investigations into

the role of Tie2 in EC behavior.