Angiogenesis and Remodeling of Airway Vasculature in Chronic Inflammation

Abstract

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.

Pulmonary vascular changes in asthma and COPD

“…Further studies in subjects with asthma were the first to confirm that changes in the airway vasculature are associated with remodelling of the airway wall [7,8]. Vessels within the submucosa plexus have since 13 then been reported extensively to be increased in the asthmatic airway.…”

“…Thickening of the airway wall in asthma also includes increased vessel calibre as a result of dilatation of capillary vessels, angiogenesis, oedema from microvascular leakage, increased capillary permeability and engorgement of lymphatic and blood capillaries. More recently, several reports with asthmatic subjects and in vivo animal models have confirmed these changes in the vascularisation of asthmatic airways with an increased number of vessels, increased size of vessels in the airway walls, increased vascular permeability, angiogenesis, increased vascular leakage and oedema partly due to the immature newly formed blood vessels which are leaky [5][6][7][8]. Some of these changes to the microvasculature are related to increased blood flow in asthmatic subjects [77] and associated with asthma severity [78].…”

“…Asthma studies were the first to confirm that changes in the bronchial vasculature are associated with remodelling of the airway wall [4][5][6][7][8]. Thereafter, a number of studies reported the involvement of specific growth factors, such as fibroblast growth factor (FGF), transforming growth factor (TGF) β1 and vascular endothelial growth factor (VEGF), during vascular remodelling in asthma and COPD [9][10][11][12].…”

Intrinsic pro-angiogenic status of cystic fibrosis airway epithelial cells

“…The only available data described an excess of angiogenesis in CF polyps and elevated levels of VEGF in the serum of cystic fibrosis patients [5,6]. Angiogenesis and vascular remodeling are key elements participating in tissue remodeling in various chronic airway inflammatory diseases such as asthma and chronic bronchitis [4,13]. Such alterations in the microvasculature largely contribute to the pathophysiology of chronic inflammatory airway diseases.…”

“…Along with the angiogenic process, microvascular remodeling is known to be a key feature of inflammatory diseases [13]. This process involves structural alterations, usually enlargement of arterioles, capillaries or venules.…”