Genistein rescues hypoxia-induced pulmonary arterial hypertension through estrogen receptor and β-adrenoceptor signaling.

Pulmonary vascular remodeling is an important pathological feature of pulmonary arterial hypertension (PAH), which is characterized by thickening of the medial smooth muscle layer. Hypertrophy of pulmonary artery smooth muscle cells (PASMCs) participates in the development of medial thickening. Genistein can attenuate PAH and inhibit medial thickening of pulmonary arteries. Since hypoxia is one of the main causes of pulmonary hypertension, this study aims to investigate the mechanism of genistein in inhibiting hypertrophic responses in PASMCs induced by hypoxia. Cells isolated from the chick embryo were cultured with or without genistein and subjected to hypoxia or not. The increase of cell surface area and α-smooth muscle actin (α-SMA) of PASMCs was significantly suppressed by genistein during hypoxia. This result was confirmed by the incorporation of puromycin into peptide chains and flow cytometry analysis. Constrained mRNA and protein hypoxia-inducible factor (HIF)-1α expression was improved by genistein under hypoxia condition. Genistein restored redox homeostasis by fluorescent probe determination. The effect of genistein on hypertrophic response was blocked by estrogen receptor inhibitor, β1-adrenoceptor agonist and β2-adrenoceptor antagonist. In conclusion, genistein potently attenuates hypoxia-induced hypertrophy of PASMCs, which may enable a novel therapy for PAH.