Aryl hydrocarbon receptor agonists upregulate VEGF secretion from bronchial epithelial cells

Abstract

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.

Keywords: Airway epithelial cells; Airway remodeling; Aryl hydrocarbon receptor; Asthma; Chronic obstructive pulmonary disease; Vascular endothelial growth factor.