PM2.5 causes vascular hyperreactivity through the upregulation of the thromboxane A(2) receptor and activation of MAPK pathways

Airborne fine particulate matter (PM2.5) is a major cardiovascular disease environmental risk factor. However, the underlying mechanism of action is not fully understood. Thromboxane is widely known as an important vasoconstrictor substance that binds to G-protein-coupled receptors (GPCR) in arteries and is involved in various cardiovascular diseases. This study examined the effect of PM2.5 on thromboxane A(2) receptor (TP) in the mesenteric arteries and the underlying intracellular signal mechanisms (by focusing on the mitogen-activated protein kinase (MAPK) pathway). Rat mesenteric artery segments were exposed to PM2.5 in the presence of MAPK pathway inhibitors. The contractile reactivity of mesenteric arteries was analyzed using wire myography. The mRNA and protein expression of TP receptor and MAPK pathway molecules were detected by real-time PCR and Western blot. Mesenteric artery receptor localization was assessed by immunohistochemistry. The results showed that TP receptor-mediated maximum contraction response was achieved after exposing arteries to 1.0 mu g/mL PM2.5 for 16 h (Emax: 228 +/- 16% of K+). Moreover, inhibitor U0126 (ERK1/2 inhibitor), SB203580 (p38 inhibitor), and SP600125 (JNK inhibitor) depressed the increased TP receptor-mediated contractile responses (reduced rage were 17.9 similar to 59.6%). These inhibitors also decreased the increased mRNA expression and protein of the TP receptor induced by PM2.5 (reduced by more than 50% and 46%, respectively). The immunoreactivity of increased TP receptor expression was primarily localized in the cytoplasm. In addition, phosphorylation quantitative analysis showed that in the presence of MAPK inhibitors, the PM2.5-induced phosphorylation of ERK1/2, p38, and JNK protein increased by more than 30.0 similar to 130.3%. These results suggest that PM2.5 upregulates the TP receptor of rat mesenteric arteries through activation of the ERK1/2, p38, and JNK MAPK pathways.