Induction of angiogenesis by airway smooth muscle from patients with asthma.
BACKGROUND
Airway remodeling in asthma involves accumulation of airway smooth muscle (ASM) and increased vascularity due to angiogenesis. Bronchial blood vessels and ASM are found in close proximity, and ASM releases multiple proinflammatory mediators, including vascular endothelial growth factor (VEGF).


OBJECTIVE
We examined whether release of proangiogenic mediators is increased in ASM from subjects with asthma and whether this is translated to induction of angiogenesis.


METHODS
Biopsy-derived ASM cells were cultured from 12 subjects with mild asthma, 8 with moderate asthma, and 9 healthy control subjects. Angiogenesis induced by cell-conditioned medium (CM) from ASM was evaluated in a tubule formation assay. Anti-CD31-labeled tubules were quantified by image analysis. Angiogenic factors in CM were quantified by antibody arrays and by enzyme-linked immunosorbent assay.


RESULTS
Induction of angiogenesis by CM from unstimulated ASM was increased in subjects with mild asthma (twofold) and moderate asthma (threefold), compared with healthy CM (P < 0.001). Levels of angiogenic factors (VEGF, angiopoietin [Ang]-1, angiogenin) were similarly elevated in CM from subjects with asthma compared with that from healthy subjects (P < 0.05), whereas antiangiogenic factors (endostatin, Ang-2) were unchanged. VEGF, Ang-1, and angiogenin in combination increased vascularity (twofold, P < 0.01) in cultured intact biopsies. Selective VEGF immunodepletion abolished enhanced tubule formation by CM from asthmatic ASM (P < 0.01), but CM depletion of Ang-1 or angiogenin had no effect.


CONCLUSIONS
ASM cultured from subjects with mild or moderate asthma, but not from healthy control subjects, promotes angiogenesis in vitro. This proangiogenic capacity resides in elevated VEGF release and suggests that ASM regulates airway neovascularization in asthma.
Simcock
David E
DE
Division of Asthma, Allergy, and Lung Biology, King's College London, Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom.
Kanabar
Varsha
V
Clarke
Graham W
GW
Mahn
Katharina
K
Karner
Charlotta
C
O'Connor
Brian J
BJ
Lee
Tak H
TH
Hirst
Stuart J
SJ
D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D042501:Angiogenic Proteins / Q000378:metabolism*; D042683:Angiopoietin-1; D001249:Asthma / Q000503:physiopathology*; D001980:Bronchi / Q000098:blood supply / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009389:Neovascularization, Pathologic; D040081:Protein Array Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D042501:Angiogenic Proteins; D042683:Angiopoietin-1; D042461:Vascular Endothelial Growth Factor A