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Induction of Angiogenesis by Airway Smooth Muscle From Patients with Asthma

¹ 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

Correspondence and requests for reprints should be addressed to Stuart J. Hirst, Ph.D., Department of Physiology, Monash University, Building 13F, Clayton Campus, Melbourne Victoria 3800, Australia. E-mail: stuart.hirst{at}med.monash.edu.au

Rationale: 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).

Objectives: 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.

Measurements and Main 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.

Key Words: airway smooth muscle • airway wall vascular remodeling • angiogenesis • asthma • vascular endothelial growth factor

AT A GLANCE COMMENTARY Scientific Knowledge on this Subject The cell types regulating airway wall angiogenesis in asthma are unknown. What This Study Adds to the Field We demonstrate that airway smooth muscle cells from subjects with mild or moderate asthma can initiate and sustain angiogenesis in vitro and that release of vascular endothelial growth factor accounts for this activity.