Chronic airway diseases, such as
asthma and
chronic obstructive pulmonary disease, are characterized by
airway remodeling.
Vascular endothelial growth factor (
VEGF) is a critical regulator of angiogenesis and
vascular remodeling, important components of
airway remodeling. The
aryl hydrocarbon receptor (AhR) is the principle receptor for many environmental toxicants, such as
2,3,7,8-tetrachlorodibenzo-p-dioxin (
TCDD), which may contribute to the pathogenesis of
asthma and
chronic obstructive pulmonary disease. However, the regulatory role of AhR on the expression of
VEGF in bronchial epithelial cells (BECs) remains elusive. This study was conducted to determine the role of AhR in regulating bronchial epithelial
VEGF expression, which might contribute to angiogenesis of
airway remodeling. The plasma
VEGF levels of asthmatic patients and healthy subjects were compared. By treating HBE-135, Beas-2B, and primary human BECs with AhR agonists, the mechanisms through which AhR modulated
VEGF expression in human BECs were investigated. The plasma
VEGF level was significantly higher in asthmatic patients than in healthy subjects. AhR agonists significantly upregulated
VEGF secretion from human BECs, which promoted the migratory and tube-forming ability of human umbilical vein endothelial cells. The secretion of
VEGF was increased via a canonical AhR pathway, followed by the 15-LOX/15-
HETE/STAT3 pathway. C57BL/6JNarl mice treated with
TCDD intratracheally also showed increased
VEGF expression in BECs. This hitherto unrecognized pathway may provide a potential target for the treatment of
airway remodeling in many
pulmonary diseases, especially those related to environmental toxicants.
KEY MESSAGE: AhR agonists increase
VEGF secretion from bronchial epithelial cells. The mechanism involves the canonical AhR pathway and 15-LOX/15-
HETE/STAT3 pathway. Asthmatic patients have higher plasma
VEGF level. Mice treated with intratracheal
TCDD show increased
VEGF expression in BECs. This novel regulatory pathway is a potential target for treating
asthma and
COPD.