Connexin-43 expression is increased by the nerve growth factor (NGF) and contributes to pulmonary arterial altered reactivity in pulmonary hypertension

Introduction We previously showed that NGF plays a pivotal role in pulmonary hypertension (PH), contributing to pulmonary arterial inflammation, remodelling and altered reactivity. Others and we have also shown a role of connexin-based GAP junctions in PH. Objective Since NGF modulates connexin-43 (Cx43) expression/activity in neuronal cells, we wondered whether NGF may alter Cx43 expression in pulmonary arteries (PA) and whether these alterations may contribute to NGF pathophysiological effects in PH. Methods Control rat PA and control human pulmonary arterial smooth muscle (hPASMC) or endothelial cells (hPAEC) were treated with NGF (0–100 ng/ml, 24 h). In vivo, experimental PH in the rat was induced by chronic hypoxia (CH, 0.5 atm, 28 days), with anti-NGF blocking antibodies (10 μg/kg ip) administered as a preventive treatment. Cx43 expression in rat PA and human cells was assessed by Western blotting. Contractions of control rat PA were induced ex vivo by phenylephrine (PHE, 10-10-10-4M) in absence or presence of NGF (100 ng/ml, 24 h). Results Cx43 expression was significantly increased by NGF ex vivo in rat PA ( P P P P Conclusions Our results show that NGF increases Cx43 expression in PA through activation of its TrkA receptor and a PI3K/ERK-dependent signalling pathway. This mechanism seems to participate in NGF-induced PA hyperreactivity and may thus contribute to PH pathophysiology.