Angiogenesis and microvascular remodeling are known features of chronic inflammatory diseases such as
asthma and
chronic bronchitis, but the mechanisms and consequences of the changes are just beginning to be elucidated. In a model of chronic airway
inflammation produced by Mycoplasma pulmonis
infection of the airways of mice or rats, angiogenesis and microvascular remodeling create vessels that mediate leukocyte influx and leak
plasma proteins into the airway mucosa. These vascular changes are driven by the immune response to the organisms. Plasma leakage results from gaps between endothelial cells, as well as from increased vascular surface area and probably other changes in the newly formed and remodeled blood vessels. Treatment with long-acting beta2 agonists can reduce but not eliminate the plasma occurring after
infection. In addition to the elevated baseline leakage, the remodeled vessels in the airway mucosa are abnormally sensitive to
substance P, but not to
platelet-activating factor or
serotonin, suggesting that the
infection leads to a selective upregulation of NK1 receptors on the vasculature. The formation of new vessels and the remodeling of existing vessels are likely to be induced by multiple
growth factors, including
vascular endothelial growth factor (
VEGF) and
angiopoietin 1 (Ang1).
VEGF increases vascular permeability, but Ang1 has the opposite effect. This feature is consistent with evidence that
VEGF and Ang1 play complementary and coordinated roles in vascular growth and remodeling and have powerful effects on vascular function. Regulation of vascular permeability by
VEGF and Ang1 may be their most rapid and potent actions in the adult, as these effects can occur independent of their effects on angiogenesis and
vascular remodeling. The ability of Ang1 to block plasma leakage without producing angiogenesis may be therapeutically advantageous. Furthermore, because
VEGF and Ang1 have additive effects in promoting angiogenesis but opposite effects on vascular permeability, they could be used together to avoid the formation of leaky vessels in therapeutic angiogenesis. Finally, the elucidation of the protective effect of Ang1 on blood vessel leakiness to
plasma proteins raises the possibility of a new strategy for reducing airway
edema in inflammatory airway diseases such as
asthma and
chronic bronchitis.