Angiogenesis and remodeling of airway vasculature in chronic inflammation.
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.
McDonald
D M
DM
Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, California 94143-0130, USA. dmcd@itsa.ucsf.edu
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D042683:Angiopoietin-1; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D001991:Bronchitis / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002199:Capillary Permeability; D002908:Chronic Disease; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000502:physiology / Q000627:therapeutic use; D004727:Endothelium / Q000166:cytology / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000098:blood supply*; D008222:Lymphokines / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D009330:Nebulizers and Vaporizers; D009389:Neovascularization, Pathologic; D011019:Pneumonia, Mycoplasma / Q000150:complications; D011412:Propanolamines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012106:Research; D020545:Respiratory Mucosa / Q000098:blood supply; D000068299:Salmeterol Xinafoate; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000319:Adrenergic beta-Antagonists; D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; C467629:Angpt1 protein, rat; D001993:Bronchodilator Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D008562:Membrane Glycoproteins; D011412:Propanolamines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C026777:ICI 118551; D000068299:Salmeterol Xinafoate; D000420:Albuterol