Chronic real-time particulate matter exposure causes rat pulmonary arteriole hyperresponsiveness and remodeling: The role of ET_BR-ERK1/2 signaling

Exposure to air pollution is associated with the incidence of respiratory diseases. The present study evaluated the pulmonary vascular system injury by chronic real-time particulate matter (PM₁₀) exposure and investigated the underlying mechanisms. Rats were exposed to PM₁₀ or filtered air for 2 to 4 months using a whole body exposure system, and intraperitoneally injected with the MEK1/2 inhibitor U0126. Right heart catheterization and myography were performed to detect lung function and pulmonary vascular reactivity, respectively. Western blotting, qRT-PCR, enzyme-linked immunosorbent assay and histological analyses were used to detect the effects and mechanisms by which PM₁₀ exposure-induced pulmonary vascular dysfunction. Functional experiment results showed that PM₁₀ exposure increased the pulmonary artery pressure of rats and caused endothelin B receptor (ET_BR)-mediated pulmonary arteriole hyperreactivity. U0126 significantly rescued these pathological changes. PM₁₀ exposure upregulated the contractile ET_BR of pulmonary arteriolar smooth muscle, and damaged pulmonary artery endothelial cells to induce the release of more endothelin 1 (ET-1). The upregulated ET_BR bound to increased ET-1 induced pulmonary arteriolar hyperresponsiveness and remodeling. U0126 inhibited the PM₁₀ exposure-induced upregulation of ET_BR in pulmonary arteriole, ET_BR-mediated pulmonary arterial hyperresponsiveness and vascular remodeling. In conclusion, chronic real-time particulate matter exposure can activate the ERK1/2 signaling, thereby inducing the upregulation of contractile ET_BR in pulmonary arteriole, which may be involved in pulmonary arteriole hyperresponsiveness and remodeling in rats. These findings provide new mechanistic evidence of PM₁₀ exposure-induced respiratory diseases, and a new possible target for treatment.