Angiopoietin-2-Driven Vascular Remodeling in Airway Inflammation

Abstract

Vascular remodeling is a feature of chronic inflammation during which capillaries transform into venules that expand the region of the vasculature in which leakage and leukocyte emigration both occur. Recently, we found that angiopoietin/Tie2 receptor signaling drives the transformation of capillaries into venules at an early stage of the sustained inflammatory response in the airways of mice infected with Mycoplasma pulmonis. However, the precise contributions of both angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) are not clear. In this study, we sought to determine the contribution of Ang2 to this vascular remodeling. Ang2 mRNA expression levels increased and phosphorylated Tie2 immunoreactivity in mucosal blood vessels decreased, indicative of diminished receptor signaling after infection. Selective inhibition of Ang2 throughout the infection by administration of either of two distinct functionblocking antibodies reduced the suppression of Tie2 phosphorylation and decreased the remodeling of mucosal capillaries into venules, the amount of leukocyte influx, and disease severity. These findings are consistent with Ang2 acting as an antagonist of Tie2 receptors and the reduction of Tie2 phosphorylation in endothelial cells rendering the vasculature more responsive to cytokines that promote both vascular remodeling and the consequences of inflammation after M. pulmonis infection. By blocking such changes, Ang2 inhibitors may prove beneficial in the treatment of sustained inflammation in which vascular remodeling, leakage, and leukocyte influx contribute to its pathophysiology.

Angiopoietin-2 promotes myeloid cell infiltration in a β2-integrin–dependent manner

“…6 Similarly, Ang-2 blockade using 2 different antibodies decreased the influx of inflammatory cells in a model of airway inflammation. 28 However, until now, there was no physiologic evidence that Ang-2 will actually promote inflammation. Within the study described here, we provide clear evidence that enduring endothelial expression of Ang-2 in transgenic mice led to profound recruitment of inflammatory cells.…”

Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation

“…The remodeling is initiated by multiple cytokines, including VEGF, TNF-α, and the angiopoietins, angiopoietin-1 (ANG1, also known as ANGPT1) and ANG2 (also known as ANGPT2) (1)(2)(3)(4).…”

“…ANG2 competitively inhibits the action of ANG1 on Tie2 (7,15) and promotes vascular remodeling by suppression of Tie2 signaling (4,(16)(17)(18)(19). ANG2 overexpression causes embryonic lethality similar to deletion of Ang1 or Tie2 (15).…”

“…ANG1 dominates in quiescent blood vessels, but ANG2 plays important roles in inflammation, sepsis, and other pathological conditions (18,(24)(25)(26) and is rapidly released from endothelial cells by inflammatory stimuli (27,28). The effects of ANG2 are greatly amplified by TNF-α and other inflammatory cytokines (4,16,17,27). ANG2 inhibitors can reduce vascular remodeling and inflamAngiopoietin-2 (ANG2) regulates blood vessel remodeling in many pathological conditions through differential effects on Tie2 signaling.…”

Dynamics of Airway Blood Vessels and Lymphatics: Lessons from Development and Inflammation

“…Both involve endothelial cell proliferation and often occur together but represent different vascular responses and have different driving factors and consequences. Unlike angiogenesis, wherein new blood vessels grow from existing ones, microvascular remodeling examined in preclinical models involves changes in endothelial cell phenotype and structural alterations, such as vascular enlargement or transformation of capillaries into venules, without the formation of new blood vessels (8)(9)(10). The microvasculature undergoes progressive changes in structure and function as conditions worsen and disease processes evolve.…”