Angiopoietin/Tie2 signaling transforms capillaries into venules primed for leukocyte trafficking in airway inflammation.
Vascular endothelial growth factor (VEGF) is a key angiogenic factor in tumors, but less is known about what drives vascular remodeling in inflammation, where plasma leakage and leukocyte influx are prominent features. In chronic airway inflammation in mice infected by the bacterium Mycoplasma pulmonis (M. pulmonis), the segment of the microvasculature that supports leukocyte adhesion and migration expands through remodeling of capillaries into vessels with features of venules. Here, we report that the angiopoietin/Tie2 pathway is an essential driving force for capillary remodeling into venules in M. pulmonis-infected mouse airways. Similar to M. pulmonis infection, systemic overexpression of angiopoietin-1 (Ang1) resulted in remodeling of airway capillaries into venular-like vessels that expressed venous markers like P-selectin, ICAM-1, and EphB4 and were sites of leukocyte adhesion during lipopolysaccharide-induced acute inflammation. Ang1 and Ang2 protein increased in M. pulmonis-infected mouse airways but came from different cellular sources: Ang1 was expressed in infiltrating neutrophils and Ang2 in endothelial cells. Indeed, systemic administration of soluble Tie2 inhibited capillary remodeling, induction of venous markers, and leukocyte influx in M. pulmonis-infected mouse airways. Together, these findings suggest that blockade of the Ang/Tie2 pathway may represent a therapeutic approach in airway inflammation.
Department of Anatomy, University of California San Francisco, San Francisco, CA 94143-0452, USA.
Jonas
J
Fuxe
Erin
E
Lashnits
Shaun
S
O'Brien
Peter
P
Baluk
Sebastien P
SP
Tabruyn
Frank
F
Kuhnert
Calvin
C
Kuo
Gavin
G
Thurston
Donald M
DM
McDonald
D000256:Adenoviridae / Q000378:metabolism; D042683:Angiopoietin-1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002196:Capillaries / Q000378:metabolism*; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007962:Leukocytes / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D045803:Mycoplasma pulmonis / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014699:Venules / Q000378:metabolism
D042683:Angiopoietin-1; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D042787:Receptor, TIE-2