Hypoxia induces endothelial-mesenchymal transition in pulmonary vascular remodeling

Abstract

It is well established that hypoxia induces epithelial-mesenchymal transition in vitro and in vivo. However, the role of hypoxia in endothelial-mesenchymal transition (EndMT), an important process in the pathogenesis of pulmonary hypertension, is not well-characterized. The present study demonstrated a significant downregulation of the endothelial marker CD 31 and its co-localization with a mesenchymal marker, α-smooth muscle actin (α-SMA), in the intimal layer of small pulmonary arteries of rats exposed to chronic hypoxia. These results suggest a possible role of hypoxia in inducing EndMT in vivo. Consistent with these observations, pulmonary microvascular endothelial cells (PMVECs) cultured under hypoxic conditions exhibited a significant decrease in CD 31 expression, alongside a marked increase in the expression of α-SMA and two other mesenchymal markers, collagen (Col) 1A1 and Col3A1. In addition, hypoxia promoted the proliferation and migration of α-SMA-expressing mesenchymal-like cells, but not of PMVECs. Of note, knockdown of hypoxia-inducible factor 1α (HIF-1α) effectively inhibited hypoxic induction of α-SMA, Col1A1 and the transcription factor Twist1, while rescuing hypoxic suppression of CD 31; these results suggest that HIF-1α is essential for hypoxia-induced EndMT and that it serves as an upstream regulator of Twist1. Mechanistically, HIF-1α was identified to bind to the promoter of the Twist1 gene, thus activating Twist1 transcription and regulating EndMT. Collectively, the present results indicate that the HIF-1α/Twist1 pathway has a critical role in mediating the effect of hypoxia-induced EndMT in pulmonary arterial remodeling.