Short-term mechanisms activated by the nerve growth factor NGF to induce pulmonary arterial hyperreactivity - 09/03/22

Doi : 10.1016/j.rmr.2022.02.029 
G. Cardouat 1, 2, , M. Douard 1, 2, C. Bouchet 1, 2, Z. Kmecová 3, P. Robillard 1, 2, F. Delcambre 4, R. Marthan 1, 2, 4, B. Muller 1, 2, C. Guibert 1, 2, V. Freund-Michel 1, 2
1 Inserm U1045, Centre de recherche Cardio-Thoracique de Bordeaux, France 
2 Université de Bordeaux, France 
3 Département de Pharmacologie et de Toxicologie, Université Comenius, Bratislava, Slovaquie 
4 CHU de Bordeaux, France 

Corresponding author.



We have previously shown a pathophysiological role for NGF in pulmonary hypertension, particularly in pulmonary arterial (PA) hyperreactivity. Our experiments have suggested different mechanisms activated by NGF depending on a short–or a long-term PA treatment. The aim of the present study was to determine the mechanisms activated after a NGF short–term PA treatment (1h) leading to PA hyperreactivity.


Basal and agonist-induced calcium responses were evaluated in vitro in primary rat PA smooth muscle cells (rPASMC) using calcium imaging (Fura-2, Fluo-4), in the absence or presence of NGF (100ng/ml, 1h). Calcium sources involved in NGF-increased calcium responses were determined using endoplasmic reticulum calcium stores depleters (thapsigargin, 1μM or cyclopiazonic acid, 10μM), or a calcium–free extracellular medium. NGF–induced phosphorylation of myosin phosphatase target subunit 1 (MYPT1) was evaluated in vitro by Western blotting in primary human PA smooth muscle cells (hPASMC). Contractions of rat PA were induced ex vivo by endothelin-1 (ET-1, 10-12–10-6M) or phenylephrine (PHE, 10-10–10-6M) in the absence or presence of NGF (100ng/ml, 1h), with or without K252a (TrkA kinase inhibitor, 300nM) or Y–27632 (Rho-associated protein kinase -ROCK-inhibitor, 10μM).


In vitro, NGF short-term treatment increases both basal and agonist-induced intracellular calcium responses in rPASMC, with endoplasmic reticulum being the main calcium source contributing to these effects. In addition, short–term treatment with NGF induced MYPT1 phosphorylation in hPASMC, involving a TrkA/ROCK-dependent pathway. Ex vivo, short-term treatment with NGF increased rat PA reactivity to PHE and ET–1. This effect was totally abolished after treatment with K252a or Y-27632.


In conclusion, our results show that NGF can induce PA hyperreactivity through activation of its TrkA receptor, leading to both modulation of calcium intracellular responses and activation of ROCK-dependent calcium sensitization mechanisms. Such mechanisms may therefore contribute to NGF-dependent PA hyperreactivity in pulmonary hypertension.

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Keyword : Circulation


© 2022  Publié par Elsevier Masson SAS.

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Vol 39 - N° 2

P. 120 - février 2022 Retour au numéro
Article précédent Article précédent
  • IL-1? increased secretion may contribute to NGF-dependent pulmonary arterial remodelling and inflammation
  • C. Bouchet, G. Cardouat, P. Fernandes, P. Robillard, F. Delcambre, R. Marthan, V. Freund-Michel
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