Expression and role of the nerve growth factor NGF in pulmonary hypertension

Introduction: Our previous studies showed an increased NGF expression in animal models of pulmonary hypertension (PH) and suggested a role for NGF in various aspects of this disease. We have studied here expression of NGF and its receptors in human PH, and investigated whether administrating anti-NGF blocking antibodies in vivo prevented some pathological aspects in a rat PH model. Methods: NGF and inflammatory cytokine secretion was assessed by ELISA in human pulmonary arteries (PA) from controls or from patients with secondary PH. Expression of NGF receptors (TrkA and p75NTR) was assessed by Western blotting. In the rat, PH was induced by monocrotaline (MCT, J1, 60mg/kg ip), with or without administration of anti-NGF blocking antibodies (J0, J2, J7, 10μg/kg ip). Pulmonary arterial pressure (Pap) and Fulton index were assessed at J28. PA medial wall thickness was evaluated on lung sections after hematoxylin and eosin staining. PA reactivity to phenylephrine or prostaglandin F2α (PGF2α) was assessed ex vivo. Results: Significant increase in expression of NGF and its receptors was observed in PA from patients with secondary PH compared to controls. In the MCT-treated rat, anti-NGF blocking antibodies significantly reduced Pap, Fulton index, cytokine secretion, PA medial wall thickness, and totally prevented PA hyperreactivity to phenylephrine or PGF2α. Conclusion: Our data show that expression of NGF and its receptors are increased in human PH. Moreover, administration of anti-NGF blocking antibodies in the rat in vivo partially prevented PH by modulating PA hyperreactivity, inflammation and remodelling. These results therefore confirm that targeting NGF may be of therapeutical interest in this disease.